references_new.bib

@misc{Bilal_2021_Circulation_143_2025,
	address = {United States},
	article-doi = {10.1161/CIRCULATIONAHA.120.052437},
	author = {Bilal, Alina S. and Blackwood, Erik A. and Thuerauf, Donna J. and Glembotski, Christopher C.},
	electronic-issn = {1524-4539},
	electronic-publication = {20210517},
	history = {2021/05/18 06:00 [medline]},
	issue = {20},
	journal = {Circulation},
	keywords = {adeno-associated virus, cardiac, heart atria, heart ventricle, myocytes, tissue specificity},
	language = {eng},
	linking-issn = {0009-7322},
	location-id = {10.1161/CIRCULATIONAHA.120.052437 [doi]},
	month = {May},
	nlm-unique-id = {0147763},
	owner = {NLM},
	pages = {2025--2027},
	publication-status = {ppublish},
	revised = {20210517},
	source = {Circulation. 2021 May 18;143(20):2025-2027. doi: 10.1161/CIRCULATIONAHA.120.052437. Epub 2021 May 17.},
	status = {In-Data-Review},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Optimizing Adeno-Associated Virus Serotype 9 for Studies of Cardiac Chamber-Specific Gene Regulation.},
	title-abbreviation = {Circulation},
	volume = {143},
	year = {2021}
}

@article{Marsh_2021_AmJPhysiolHeartCircPhysiol_320_H1813,
	abstract = {Although peroxisomes have been extensively studied in other cell types, their presence and function have gone virtually unexamined in cardiac myocytes. Here, in neonatal rat ventricular myocytes (NRVM) we showed that several known peroxisomal proteins co-localize to punctate structures with a morphology typical of peroxisomes. Surprisingly, we found that the peroxisomal protein, fatty acyl-CoA reductase 1 (FAR1), was upregulated by pharmacological and pathophysiological ER stress induced by tunicamycin (TM) and simulated ischemia-reperfusion (sI/R), respectively. Moreover, FAR1 induction in NRVM was mediated by the ER stress sensor, activating transcription factor 6 (ATF6). Functionally, FAR1 knockdown reduced myocyte death during oxidative stress induced by either sI/R or hydrogen peroxide (H(2)O(2)). Thus, Far1 is an ER stress-inducible gene, which encodes a protein that localizes to peroxisomes of cardiac myocytes, where it reduces myocyte viability during oxidative stress. Since FAR1 is critical for plasmalogen synthesis, these results imply that plasmalogens may exert maladaptive effects on the viability of myocytes exposed to oxidative stress.NEW \& NOTEWORTHY The peroxisomal enzyme, FAR1, was shown to be an ER stress- and ATF6-inducible protein that localizes to peroxisomes in cardiac myocytes. FAR1 decreases myocyte viability during oxidative stress.},
	article-doi = {10.1152/ajpheart.00999.2020},
	article-pii = {H-00999-2020},
	author = {Marsh, Kayleigh G. and Arrieta, Adrian and Thuerauf, Donna J. and Blackwood, Erik A. and MacDonnell, Lauren and Glembotski, Christopher C.},
	completed = {20210510},
	electronic-issn = {1522-1539},
	electronic-publication = {20210305},
	grantno = {R01 HL149931/HL/NHLBI NIH HHS/United States},
	history = {2021/03/05 12:10 [entrez]},
	issue = {5},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Aldehyde Oxidoreductases/*biosynthesis/genetics, Animals, Animals, Newborn, Cell Hypoxia, Cell Survival, Cells, Cultured, *Endoplasmic Reticulum Stress/drug effects, Enzyme Induction, Hydrogen Peroxide/toxicity, Myocardial Reperfusion Injury/*enzymology/genetics/pathology, Myocytes, Cardiac/drug effects/*enzymology/pathology, Oxidative Stress, Peroxisomes/drug effects/*enzymology/metabolism, Rats, Tunicamycin/toxicity, *ATF6, *FAR1, *cardiomyocyte, *ischemia-reperfusion, *peroxisome},
	language = {eng},
	linking-issn = {0363-6135},
	location-id = {10.1152/ajpheart.00999.2020 [doi]},
	month = {May},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H1813--H1821},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {EC 1.2.- (Far1 protein, rat)},
	revised = {20210610},
	source = {Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H1813-H1821. doi: 10.1152/ajpheart.00999.2020. Epub 2021 Mar 5.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {The peroxisomal enzyme, FAR1, is induced during ER stress in an ATF6-dependent manner in cardiac myocytes.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {320},
	year = {2021}
}

@article{Blackwood_2020_Journalofvisualizedexperiments:JoVE__,
	abstract = {The isolation and culturing of cardiac myocytes from mice has been essential for furthering the understanding of cardiac physiology and pathophysiology. While isolating myocytes from neonatal mouse hearts is relatively straightforward, myocytes from the adult murine heart are preferred. This is because compared to neonatal cells, adult myocytes more accurately recapitulate cell function as it occurs in the adult heart in vivo. However, it is technically difficult to isolate adult mouse cardiac myocytes in the necessary quantities and viability, which contributes to an experimental impasse. Furthermore, published procedures are specific for the isolation of either atrial or ventricular myocytes at the expense of atrial and ventricular non-myocyte cells. Described here is a detailed method for isolating both atrial and ventricular cardiac myocytes, along with atrial and ventricular non-myocytes, simultaneously from a single mouse heart. Also provided are the details for optimal cell-specific culturing methods, which enhance cell viability and function. This protocol aims not only to expedite the process of adult murine cardiac cell isolation, but also to increase the yield and viability of cells for investigations of atrial and ventricular cardiac cells.},
	address = {United States},
	article-doi = {10.3791/61224},
	author = {Blackwood, Erik A. and Bilal, Alina S. and Azizi, Khalid and Sarakki, Anup and Glembotski, Christopher C.},
	completed = {20201026},
	electronic-issn = {1940-087X},
	electronic-publication = {20200614},
	grantno = {R01 HL141463/HL/NHLBI NIH HHS/United States},
	history = {2020/10/27 06:00 [medline]},
	issue = {160},
	journal = {Journal of visualized experiments : JoVE},
	keywords = {Aging, Animals, Cell Culture Techniques/instrumentation/*methods, Cell Separation/*methods, Cell Survival, Cells, Cultured, Heart Atria/*cytology, Heart Ventricles/*cytology, Mice, Myocytes, Cardiac/*cytology},
	language = {eng},
	linking-issn = {1940-087X},
	location-id = {10.3791/61224 [doi]},
	month = {Jun},
	nlm-unique-id = {101313252},
	owner = {NLM},
	publication-status = {epublish},
	revised = {20201026},
	source = {J Vis Exp. 2020 Jun 14;(160). doi: 10.3791/61224.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Simultaneous Isolation and Culture of Atrial Myocytes, Ventricular Myocytes, and Non-Myocytes from an Adult Mouse Heart.},
	title-abbreviation = {J Vis Exp},
	year = {2020}
}

@article{Blackwood_2020_JMolCellCardiol_143_132,
	abstract = {The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the ER stressor thapsigargin (TG), which depletes ER calcium, induced death of cultured neonatal rat ventricular myocytes (NRVMs) in high media volume but fostered protection in low media volume. In contrast, another ER stressor, tunicamycin (TM), a protein glycosylation inhibitor, induced NRVM death in all media volumes, suggesting that protective proteins were secreted in response to TG but not TM. Proteomic analyses of TG- and TM-conditioned media showed that the secretion of most proteins was inhibited by TG and TM; however, secretion of several ER-resident proteins, including GRP78 was increased by TG but not TM. Simulated ischemia, which decreases ER/SR calcium also increased secretion of these proteins. Mechanistically, secreted GRP78 was shown to enhance survival of NRVMs by collaborating with a cell-surface protein, CRIPTO, to activate protective AKT signaling and to inhibit death-promoting SMAD2 signaling. Thus, proteins secreted during ER stress mediated by ER calcium depletion can enhance cardiac myocyte viability.},
	address = {England},
	article-doi = {10.1016/j.yjmcc.2020.04.012},
	article-pii = {S0022-2828(20)30094-8},
	author = {Blackwood, Erik A. and Thuerauf, Donna J. and Stastna, Miroslava and Stephens, Haley and Sand, Zoe and Pentoney, Amber and Azizi, Khalid and Jakobi, Tobias and {Van Eyk}, Jennifer E. and Katus, Hugo A. and Glembotski, Christopher C. and Doroudgar, Shirin},
	completed = {20210712},
	electronic-issn = {1095-8584},
	electronic-publication = {20200425},
	grantno = {P01 HL112730/HL/NHLBI NIH HHS/United States},
	history = {2020/04/28 06:00 [entrez]},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Apoptosis, Autocrine Communication, Biomarkers, Calcium/metabolism, Calcium Signaling/drug effects, Cell Survival, Cells, Cultured, Disease Susceptibility, *Endoplasmic Reticulum Stress/drug effects, Epidermal Growth Factor/metabolism, Membrane Glycoproteins/metabolism, Mice, Myocytes, Cardiac/drug effects/*metabolism, Neoplasm Proteins/metabolism, Paracrine Communication, *Proteome, *Proteomics/methods, Rats, Sarcoplasmic Reticulum/metabolism, Signal Transduction/drug effects, Thapsigargin/pharmacology, *Cardiac myocyte death, *Cardiokine, *Cardioprotection, *ER stress, *Heart failure, *Proteostasis},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2020.04.012 [doi]},
	month = {Jun},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {132--144},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210712},
	source = {J Mol Cell Cardiol. 2020 Jun;143:132-144. doi: 10.1016/j.yjmcc.2020.04.012. Epub 2020 Apr 25.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {143},
	year = {2020}
}

@article{Arrieta_2020_JBiolChem_295_7566,
	abstract = {We have previously demonstrated that ischemia/reperfusion (I/R) impairs endoplasmic reticulum (ER)-based protein folding in the heart and thereby activates an unfolded protein response sensor and effector, activated transcription factor 6α (ATF6). ATF6 then induces mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER-resident protein with no known structural homologs and unclear ER function. To determine MANF's function in the heart in vivo, here we developed a cardiomyocyte-specific MANF-knockdown mouse model. MANF knockdown increased cardiac damage after I/R, which was reversed by AAV9-mediated ectopic MANF expression. Mechanistically, MANF knockdown in cultured neonatal rat ventricular myocytes (NRVMs) impaired protein folding in the ER and cardiomyocyte viability during simulated I/R. However, this was not due to MANF-mediated protection from reactive oxygen species generated during reperfusion. Because I/R impairs oxygen-dependent ER protein disulfide formation and such impairment can be caused by reductive stress in the ER, we examined the effects of the reductive ER stressor DTT. MANF knockdown in NRVMs increased cell death from DTT-mediated reductive ER stress, but not from nonreductive ER stresses caused by thapsigargin-mediated ER Ca(2+) depletion or tunicamycin-mediated inhibition of ER protein glycosylation. In vitro, recombinant MANF exhibited chaperone activity that depended on its conserved cysteine residues. Moreover, in cells, MANF bound to a model ER protein exhibiting improper disulfide bond formation during reductive ER stress but did not bind to this protein during nonreductive ER stress. We conclude that MANF is an ER chaperone that enhances protein folding and myocyte viability during reductive ER stress.},
	article-doi = {10.1074/jbc.RA120.013345},
	article-pii = {RA120.013345},
	author = {Arrieta, Adrian and Blackwood, Erik A. and Stauffer, Winston T. and {Santo Domingo}, Michelle and Bilal, Alina S. and Thuerauf, Donna J. and Pentoney, Amber N. and Aivati, Cathrine and Sarakki, Anup V. and Doroudgar, Shirin and Glembotski, Christopher C.},
	completed = {20201224},
	electronic-issn = {1083-351X},
	electronic-publication = {20200423},
	grantno = {R01 HL149931/HL/NHLBI NIH HHS/United States},
	history = {2020/04/25 06:00 [entrez]},
	issue = {22},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Cell Survival, Endoplasmic Reticulum/genetics/*metabolism/pathology, *Endoplasmic Reticulum Stress, Glycosylation, HeLa Cells, Humans, Mice, Mice, Knockout, Molecular Chaperones/genetics/*metabolism, Myocardial Reperfusion Injury/genetics/*metabolism/pathology, Myocardium/*metabolism/pathology, Myocytes, Cardiac/*metabolism/pathology, Nerve Growth Factors/genetics/*metabolism, Reactive Oxygen Species, *cardiomyocyte, *chaperone, *endoplasmic reticulum stress (ER stress), *heart function, *ischemia, *ischemia/reperfusion, *mesencephalic astrocyte-derived neurotrophic factor (MANF), *protein folding, *reductive stress, *unfolded protein response},
	language = {eng},
	linking-issn = {0021-9258},
	location-id = {10.1074/jbc.RA120.013345 [doi]},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7566--7583},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {0 (Reactive Oxygen Species)},
	revised = {20210205},
	source = {J Biol Chem. 2020 May 29;295(22):7566-7583. doi: 10.1074/jbc.RA120.013345. Epub 2020 Apr 23.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Mesencephalic astrocyte-derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart.},
	title-abbreviation = {J Biol Chem},
	volume = {295},
	year = {2020}
}

@article{Glembotski_2020_Frontiersinphysiology_11_267,
	abstract = {Proteostasis encompasses a homeostatic cellular network in all cells that maintains the integrity of the proteome, which is critical for optimal cellular function. The components of the proteostasis network include protein synthesis, folding, trafficking, and degradation. Cardiac myocytes have a specialized endoplasmic reticulum (ER) called the sarcoplasmic reticulum that is well known for its role in contractile calcium handling. However, less studied is the proteostasis network associated with the ER, which is of particular importance in cardiac myocytes because it ensures the integrity of proteins that are critical for cardiac contraction, e.g., ion channels, as well as proteins necessary for maintaining myocyte viability and interaction with other cell types, e.g., secreted hormones and growth factors. A major aspect of the ER proteostasis network is the ER unfolded protein response (UPR), which is initiated when misfolded proteins in the ER activate a group of three ER transmembrane proteins, one of which is the transcription factor, ATF6. Prior to studies in the heart, ATF6 had been shown in model cell lines to be primarily adaptive, exerting protective effects by inducing genes that encode ER proteins that fortify protein-folding in this organelle, thus establishing the canonical role for ATF6. Subsequent studies in isolated cardiac myocytes and in the myocardium, in vivo, have expanded roles for ATF6 beyond the canonical functions to include the induction of genes that encode proteins outside of the ER that do not have known functions that are obviously related to ER protein-folding. The identification of such non-canonical roles for ATF6, as well as findings that the gene programs induced by ATF6 differ depending on the stimulus, have piqued interest in further research on ATF6 as an adaptive effector in cardiac myocytes, underscoring the therapeutic potential of activating ATF6 in the heart. Moreover, discoveries of small molecule activators of ATF6 that adaptively affect the heart, as well as other organs, in vivo, have expanded the potential for development of ATF6-based therapeutics. This review focuses on the ATF6 arm of the ER UPR and its effects on the proteostasis network in the myocardium.},
	article-doi = {10.3389/fphys.2020.00267},
	author = {Glembotski, Christopher C. and Arrieta, Adrian and Blackwood, Erik A. and Stauffer, Winston T.},
	electronic-issn = {1664-042X},
	electronic-publication = {20200408},
	history = {2020/04/24 06:01 [medline]},
	journal = {Frontiers in physiology},
	keywords = {ATF6, ER stress, cardiac myocyte, proteostasis, unfolded protein response},
	language = {eng},
	linking-issn = {1664-042X},
	location-id = {267},
	nlm-unique-id = {101549006},
	owner = {NLM},
	pages = {267},
	print-issn = {1664-042X},
	publication-status = {epublish},
	revised = {20200928},
	source = {Front Physiol. 2020 Apr 8;11:267. doi: 10.3389/fphys.2020.00267. eCollection 2020.},
	status = {PubMed-not-MEDLINE},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {ATF6 as a Nodal Regulator of Proteostasis in the Heart.},
	title-abbreviation = {Front Physiol},
	volume = {11},
	year = {2020}
}

@article{Palmer_2020_ACSmedicinalchemistryletters_11_292,
	abstract = {We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of 147, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug 1 and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug 1 blocks activity of 147 by its inability to undergo metabolic oxidation by ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly here for the first time. Biological evaluation of ROS-activatable prodrug 1 in primary cardiomyocytes demonstrates protection against peroxide-mediated toxicity and enhances viability following simulated I/R injury. The ability to selectively target ATF6 activation under diseased conditions establishes the potential for localized stress-responsive signaling pathway activation as a therapeutic approach for I/R injury and related protein misfolding maladies.},
	article-doi = {10.1021/acsmedchemlett.9b00299},
	author = {Palmer, Jonathan E. and Brietske, Breanna M. and Bate, Tyler C. and Blackwood, Erik A. and Garg, Manasa and Glembotski, Christopher C. and Cooley, Christina B.},
	electronic-issn = {1948-5875},
	electronic-publication = {20191106},
	grantno = {R01 HL149931/HL/NHLBI NIH HHS/United States},
	history = {2020/03/19 06:01 [medline]},
	issue = {3},
	journal = {ACS medicinal chemistry letters},
	language = {eng},
	linking-issn = {1948-5875},
	location-id = {10.1021/acsmedchemlett.9b00299 [doi]},
	month = {Mar},
	nlm-unique-id = {101521073},
	owner = {NLM},
	pages = {292--297},
	print-issn = {1948-5875},
	publication-status = {epublish},
	revised = {20210312},
	source = {ACS Med Chem Lett. 2019 Nov 6;11(3):292-297. doi: 10.1021/acsmedchemlett.9b00299. eCollection 2020 Mar 12.},
	status = {PubMed-not-MEDLINE},
	timestamp = {2021.09.20},
	title = {Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury.},
	title-abbreviation = {ACS Med Chem Lett},
	volume = {11},
	year = {2020}
}

@article{Blackwood_2020_Cells_9_,
	abstract = {The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.},
	article-doi = {10.3390/cells9030602},
	article-pii = {cells-09-00602},
	author = {Blackwood, Erik A. and Bilal, Alina S. and Stauffer, Winston T. and Arrieta, Adrian and Glembotski, Christopher C.},
	completed = {20210308},
	electronic-issn = {2073-4409},
	electronic-publication = {20200303},
	grantno = {F31 HL140850/HL/NHLBI NIH HHS/United States},
	history = {2021/03/09 06:00 [medline]},
	issue = {3},
	journal = {Cells},
	keywords = {Activating Transcription Factor 6/*metabolism, Cardiomyopathies/*genetics, Humans, Myocytes, Cardiac/*metabolism, Proteostasis/*physiology, Unfolded Protein Response/*genetics, *ATF6, *cardiac myocyte, *cardiomyopathy, *hypertrophy, *proteostasis, *small molecule, *therapy, *transcriptional regulation, *unfolded protein response (UPR)},
	language = {eng},
	linking-issn = {2073-4409},
	location-id = {602},
	month = {Mar},
	nlm-unique-id = {101600052},
	owner = {NLM},
	publication-status = {epublish},
	registry-number = {0 (Activating Transcription Factor 6)},
	revised = {20210308},
	source = {Cells. 2020 Mar 3;9(3):602. doi: 10.3390/cells9030602.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis.},
	title-abbreviation = {Cells},
	volume = {9},
	year = {2020}
}

@article{Stauffer_2020_Internationaljournalofmolecularsciences_21_,
	abstract = {Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor β (TGFβ), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGFβ-Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of α smooth muscle actin (αSMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGFβ-Smad axis of cardiac fibroblast activation.},
	article-doi = {10.3390/ijms21041373},
	article-pii = {ijms-21-01373},
	author = {Stauffer, Winston T. and Blackwood, Erik A. and Azizi, Khalid and Kaufman, Randal J. and Glembotski, Christopher C.},
	completed = {20201130},
	electronic-issn = {1422-0067},
	electronic-publication = {20200218},
	grantno = {R01 CA198103/CA/NCI NIH HHS/United States},
	history = {2020/12/01 06:00 [medline]},
	issue = {4},
	journal = {International journal of molecular sciences},
	keywords = {Activating Transcription Factor 6/*metabolism, Animals, Biomarkers/metabolism, Endoplasmic Reticulum/drug effects/*metabolism, Fibroblasts/drug effects/*metabolism/*pathology, Fibrosis, Gene Expression Regulation/drug effects, Heart Ventricles/pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Myocardium/*pathology, Phosphorylation/drug effects, Signal Transduction/drug effects, Smad2 Protein/metabolism, Stress Fibers/drug effects/metabolism, Transforming Growth Factor beta/pharmacology, *Unfolded Protein Response, ATF6, ER stress, Smad, TGFβ, UPR, cardiac fibroblast, cardiac fibrosis, endoplasmic reticulum},
	language = {eng},
	linking-issn = {1422-0067},
	location-id = {1373},
	month = {Feb},
	nlm-unique-id = {101092791},
	owner = {NLM},
	publication-status = {epublish},
	registry-number = {0 (Transforming Growth Factor beta)},
	revised = {20201130},
	source = {Int J Mol Sci. 2020 Feb 18;21(4):1373. doi: 10.3390/ijms21041373.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts.},
	title-abbreviation = {Int J Mol Sci},
	volume = {21},
	year = {2020}
}

@article{Stauffer_2020_Internationaljournalofmolecularsciences_21_,
	abstract = {There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6α is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α.},
	article-doi = {10.3390/ijms21031134},
	article-pii = {ijms-21-01134},
	author = {Stauffer, Winston T. and Arrieta, Adrian and Blackwood, Erik A. and Glembotski, Christopher C.},
	completed = {20201130},
	electronic-issn = {1422-0067},
	electronic-publication = {20200208},
	grantno = {R01HL135893, R01 HL75573, R01 HL104535/NH/NIH HHS/United States},
	history = {2020/12/01 06:00 [medline]},
	issue = {3},
	journal = {International journal of molecular sciences},
	keywords = {Activating Transcription Factor 6/*metabolism, Animals, *Endoplasmic Reticulum Stress, Gene Expression Regulation, Humans, Myocardium/metabolism, Protein Isoforms/metabolism, Transcription Factors/metabolism, *Transcription, Genetic, ATF6α, ATF6β, ER stress, OASIS, UPR, basic leucine-zipper, cardiac, endoplasmic reticulum, proteostasis, transcriptional regulation},
	language = {eng},
	linking-issn = {1422-0067},
	location-id = {1134},
	month = {Feb},
	nlm-unique-id = {101092791},
	owner = {NLM},
	publication-status = {epublish},
	registry-number = {0 (Transcription Factors)},
	revised = {20201130},
	source = {Int J Mol Sci. 2020 Feb 8;21(3):1134. doi: 10.3390/ijms21031134.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α.},
	title-abbreviation = {Int J Mol Sci},
	volume = {21},
	year = {2020}
}

@article{Arrieta_2019_Frontiersincardiovascularmedicine_6_193,
	abstract = {The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.},
	article-doi = {10.3389/fcvm.2019.00193},
	author = {Arrieta, Adrian and Blackwood, Erik A. and Stauffer, Winston T. and Glembotski, Christopher C.},
	electronic-issn = {2297-055X},
	electronic-publication = {20200115},
	grantno = {R01 HL141463/HL/NHLBI NIH HHS/United States},
	history = {2020/02/06 06:01 [medline]},
	journal = {Frontiers in cardiovascular medicine},
	keywords = {UPR, endoplasmic reticulum, mitochondria, protein folding, proteostasis},
	language = {eng},
	linking-issn = {2297-055X},
	location-id = {193},
	nlm-unique-id = {101653388},
	owner = {NLM},
	pages = {193},
	print-issn = {2297-055X},
	publication-status = {epublish},
	revised = {20201011},
	source = {Front Cardiovasc Med. 2020 Jan 15;6:193. doi: 10.3389/fcvm.2019.00193. eCollection 2019.},
	status = {PubMed-not-MEDLINE},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart.},
	title-abbreviation = {Front Cardiovasc Med},
	volume = {6},
	year = {2019}
}

@article{Lindberg_2019_PNAS_116_19774,
	article-doi = {10.1073/pnas.1914001116},
	article-pii = {201914001},
	author = {Lindberg, Iris and Glembotski, Christopher C.},
	comment = {Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20169-20179. PMID: 31455734},
	completed = {20200319},
	electronic-issn = {1091-6490},
	electronic-publication = {20190912},
	grantno = {R56 DA005084/DA/NIDA NIH HHS/United States},
	history = {2019/09/14 06:00 [entrez]},
	issue = {40},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	keywords = {*Amides, Animals, Mice, *Peptides},
	language = {eng},
	linking-issn = {0027-8424},
	location-id = {10.1073/pnas.1914001116 [doi]},
	month = {Oct},
	nlm-unique-id = {7505876},
	owner = {NLM},
	pages = {19774--19776},
	print-issn = {0027-8424},
	publication-status = {ppublish},
	registry-number = {0 (Peptides)},
	revised = {20200319},
	source = {Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19774-19776. doi: 10.1073/pnas.1914001116. Epub 2019 Sep 12.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Physiological signaling in the absence of amidated peptides.},
	title-abbreviation = {Proc Natl Acad Sci U S A},
	volume = {116},
	year = {2019}
}

@article{Glembotski_2019_TrendsMolMed_25_538,
	abstract = {Endoplasmic reticulum (ER) stress is a pathological hallmark of numerous ischemic diseases, including stroke and myocardial infarction (MI). In these diseases, ER stress leads to activation of the unfolded protein response (UPR) and subsequent adaptation of cellular physiology in ways that dictate cellular fate following ischemia. Recent evidence highlights a protective role for the activating transcription factor 6 (ATF6) arm of the UPR in mitigating adverse outcomes associated with ischemia/reperfusion (I/R) injury in multiple disease models. This suggests ATF6 as a potential therapeutic target for intervening in diverse ischemia-related disorders. Here, we discuss the evidence demonstrating the importance of ATF6 signaling in protecting different tissues against ischemic damage and discuss preclinical results focused on defining the potential for pharmacologically targeting ATF6 to intervene in such diseases.},
	article-doi = {10.1016/j.molmed.2019.03.005},
	article-pii = {S1471-4914(19)30066-8},
	author = {Glembotski, Christopher C. and Rosarda, Jessica D. and Wiseman, R. Luke},
	completed = {20200408},
	electronic-issn = {1471-499X},
	electronic-publication = {20190508},
	grantno = {R01 HL141463/HL/NHLBI NIH HHS/United States},
	history = {2019/05/13 06:00 [entrez]},
	issue = {6},
	journal = {Trends in molecular medicine},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Animals, Biomarkers, Disease Susceptibility, Endoplasmic Reticulum Stress, Humans, Ischemia/drug therapy/*etiology/*metabolism/pathology, Molecular Targeted Therapy, Myocardial Infarction/etiology/metabolism/pathology/therapy, Organ Specificity, *Proteostasis, Signal Transduction, Unfolded Protein Response, *ATF6, *ER stress, *myocardial infarction, *stroke, *unfolded protein response},
	language = {eng},
	linking-issn = {1471-4914},
	location-id = {10.1016/j.molmed.2019.03.005 [doi]},
	manuscript-id = {NIHMS1525933},
	month = {Jun},
	nlm-unique-id = {100966035},
	owner = {NLM},
	pages = {538--550},
	print-issn = {1471-4914},
	publication-status = {ppublish},
	registry-number = {0 (Biomarkers)},
	revised = {20201103},
	source = {Trends Mol Med. 2019 Jun;25(6):538-550. doi: 10.1016/j.molmed.2019.03.005. Epub 2019 May 8.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Proteostasis and Beyond: ATF6 in Ischemic Disease.},
	title-abbreviation = {Trends Mol Med},
	volume = {25},
	year = {2019}
}

@inproceedings{Glembotski_2019__73_1807,
	article-doi = {10.1016/j.jacc.2018.12.089},
	article-pii = {S0735-1097(19)33691-5},
	author = {Glembotski, Christopher C. and Arrieta, Adrian and Blackwood, Erik A.},
	booktitle = {Journal of the American College of Cardiology},
	comment = {J Am Coll Cardiol. 2019 Apr 16;73(14):1795-1806. PMID: 30975297},
	completed = {20200214},
	electronic-issn = {1558-3597},
	grantno = {R01 HL104535/HL/NHLBI NIH HHS/United States},
	history = {2020/02/15 06:00 [medline]},
	issue = {14},
	keywords = {*Heart Diseases, Humans, *Mitochondria, Unfolded Protein Response, *cardiomyocyte, *heart, *mitochondria, *pressure overload, *unfolded protein response},
	language = {eng},
	linking-issn = {0735-1097},
	location-id = {10.1016/j.jacc.2018.12.089 [doi]},
	manuscript-id = {NIHMS1054246},
	month = {Apr},
	nlm-unique-id = {8301365},
	owner = {NLM},
	pages = {1807--1810},
	print-issn = {0735-1097},
	publication-status = {ppublish},
	revised = {20201103},
	source = {J Am Coll Cardiol. 2019 Apr 16;73(14):1807-1810. doi: 10.1016/j.jacc.2018.12.089.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Unfolding the Roles of Mitochondria as Therapeutic Targets for Heart Disease.},
	title-abbreviation = {J Am Coll Cardiol},
	volume = {73},
	year = {2019}
}

@article{Blackwood_2019_Naturecommunications_10_187,
	abstract = {Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.},
	article-doi = {10.1038/s41467-018-08129-2},
	article-pii = {8129},
	author = {Blackwood, Erik A. and Azizi, Khalid and Thuerauf, Donna J. and Paxman, Ryan J. and Plate, Lars and Kelly, Jeffery W. and Wiseman, R. Luke and Glembotski, Christopher C.},
	completed = {20190218},
	electronic-issn = {2041-1723},
	electronic-publication = {20190114},
	grantno = {R01 AG046495/AG/NIA NIH HHS/United States},
	history = {2019/02/20 06:00 [medline]},
	issue = {1},
	journal = {Nature communications},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Animals, Animals, Newborn, Cells, Cultured, Cerebral Infarction/etiology/pathology/*prevention \& control, Disease Models, Animal, Endoplasmic Reticulum/metabolism, Female, Heart Ventricles/pathology, Humans, Kidney/blood supply/pathology, Kidney Diseases/etiology/pathology/*prevention \& control, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction/etiology/pathology/*prevention \& control, Myocytes, Cardiac, Primary Cell Culture, Protective Agents/*pharmacology/therapeutic use, Proteostasis/drug effects, Rats, Reperfusion Injury/*drug therapy/etiology, Treatment Outcome, Unfolded Protein Response/drug effects},
	language = {eng},
	linking-issn = {2041-1723},
	location-id = {187},
	month = {Jan},
	nlm-unique-id = {101528555},
	owner = {NLM},
	pages = {187},
	publication-status = {epublish},
	registry-number = {0 (Protective Agents)},
	revised = {20201103},
	source = {Nat Commun. 2019 Jan 14;10(1):187. doi: 10.1038/s41467-018-08129-2.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.},
	title-abbreviation = {Nat Commun},
	volume = {10},
	year = {2019}
}

@article{Blackwood_2019_CircRes_124_79,
	abstract = {RATIONALE: Endoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating transcription factor 6α), an inducer of genes that enhance protein folding and restore ER proteostasis. Because of increased protein synthesis, it is possible that protein folding and ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes. OBJECTIVE: To examine the activity and function of ATF6 during cardiac hypertrophy. METHODS AND RESULTS: We found that ER stress and ATF6 were activated and ATF6 target genes were induced in mice subjected to an acute model of transverse aortic constriction, or to free-wheel exercise, both of which promote adaptive cardiac myocyte hypertrophy with preserved cardiac function. Cardiac myocyte-specific deletion of Atf6 (ATF6 cKO [conditional knockout]) blunted transverse aortic constriction and exercise-induced cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for ATF6 in compensatory myocyte growth. Transcript profiling and chromatin immunoprecipitation identified RHEB (Ras homologue enriched in brain) as an ATF6 target gene in the heart. RHEB is an activator of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a major inducer of protein synthesis and subsequent cell growth. Both transverse aortic constriction and exercise upregulated RHEB, activated mTORC1, and induced cardiac hypertrophy in wild type mouse hearts but not in ATF6 cKO hearts. Mechanistically, knockdown of ATF6 in neonatal rat ventricular myocytes blocked phenylephrine- and IGF1 (insulin-like growth factor 1)-mediated RHEB induction, mTORC1 activation, and myocyte growth, all of which were restored by ectopic RHEB expression. Moreover, adeno-associated virus 9- RHEB restored cardiac growth to ATF6 cKO mice subjected to transverse aortic constriction. Finally, ATF6 induced RHEB in response to growth factors, but not in response to other activators of ATF6 that do not induce growth, indicating that ATF6 target gene induction is stress specific. CONCLUSIONS: Compensatory cardiac hypertrophy activates ER stress and ATF6, which induces RHEB and activates mTORC1. Thus, ATF6 is a previously unrecognized link between growth stimuli and mTORC1-mediated cardiac growth.},
	article-doi = {10.1161/CIRCRESAHA.118.313854},
	author = {Blackwood, Erik A. and Hofmann, Christoph and {Santo Domingo}, Michelle and Bilal, Alina S. and Sarakki, Anup and Stauffer, Winston and Arrieta, Adrian and Thuerauf, Donna J. and Kolkhorst, Fred W. and M{\"u}ller, Oliver J. and Jakobi, Tobias and Dieterich, Christoph and Katus, Hugo A. and Doroudgar, Shirin and Glembotski, Christopher C.},
	comment = {Circ Res. 2019 Jan 4;124(1):9-11. PMID: 30605413},
	completed = {20191022},
	electronic-issn = {1524-4571},
	grantno = {R01 HL104535/HL/NHLBI NIH HHS/United States},
	history = {2018/12/25 06:00 [entrez]},
	issue = {1},
	journal = {Circulation research},
	keywords = {Activating Transcription Factor 6/deficiency/genetics/*metabolism, Animals, Animals, Newborn, Disease Models, Animal, Endoplasmic Reticulum/enzymology, Endoplasmic Reticulum Stress, Genetic Predisposition to Disease, Hypertrophy, Left Ventricular/*enzymology/genetics/pathology/physiopathology, Male, Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac/*enzymology/pathology, Phenotype, Protein Folding, Proteostasis, Ras Homolog Enriched in Brain Protein/genetics/*metabolism, Signal Transduction, *Transcriptional Activation, *Ventricular Function, Left, *Ventricular Remodeling, *ATF6, *ER stress, *cardiac hypertrophy, *mTORC1, *proteostasis},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.118.313854 [doi]},
	manuscript-id = {NIHMS1510057},
	month = {Jan},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {79--93},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)},
	revised = {20201103},
	source = {Circ Res. 2019 Jan 4;124(1):79-93. doi: 10.1161/CIRCRESAHA.118.313854.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {ATF6 Regulates Cardiac Hypertrophy by Transcriptional Induction of the mTORC1 Activator, Rheb.},
	title-abbreviation = {Circ Res},
	volume = {124},
	year = {2019}
}

@article{Paxman_2018_eLife_7_,
	abstract = {Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (147) was previously identified (<xref ref-type="bibr" rid="bib35">Plate et al., 2016</xref>) to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that 147-dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by 147 include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs 147-dependent induction of the ATF6-target gene, BiP, implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with 147. Thus, 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.},
	article-doi = {10.7554/eLife.37168},
	article-pii = {37168},
	author = {Paxman, Ryan and Plate, Lars and Blackwood, Erik A. and Glembotski, Chris and Powers, Evan T. and Wiseman, R. Luke and Kelly, Jeffery W.},
	completed = {20181217},
	electronic-issn = {2050-084X},
	electronic-publication = {20180807},
	grantno = {Heart Institute Inamori Foundation/San Diego State University/International},
	history = {2018/12/18 06:00 [medline]},
	journal = {eLife},
	keywords = {Activating Transcription Factor 6/*genetics, Amides/*pharmacology, Endoplasmic Reticulum/drug effects/genetics, Endoplasmic Reticulum Stress/*drug effects, HEK293 Cells, Humans, Phenylpropionates/*pharmacology, Prodrugs/*pharmacology, Signal Transduction/drug effects, Small Molecule Libraries/*pharmacology, Unfolded Protein Response/genetics, *biochemistry, *chemical biology, *cytochrome p450, *human, *protein disulfide isomerase, *proteostasis, *proteostasis regulator, *quinone methide, *reactive cysteine},
	language = {eng},
	linking-issn = {2050-084X},
	location-id = {e37168},
	month = {Aug},
	nlm-unique-id = {101579614},
	owner = {NLM},
	publication-status = {epublish},
	registry-number = {0 (Small Molecule Libraries)},
	revised = {20191101},
	source = {Elife. 2018 Aug 7;7:e37168. doi: 10.7554/eLife.37168.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins.},
	title-abbreviation = {Elife},
	volume = {7},
	year = {2018}
}

@article{Arrieta_2018_CurrTopMicrobiolImmunol_414_193,
	abstract = {Cardiac myocytes are the cells responsible for the robust ability of the heart to pump blood throughout the circulatory system. Cardiac myocytes grow in response to a variety of physiological and pathological conditions; this growth challenges endoplasmic reticulum-protein quality control (ER-PQC), a major feature of which includes the unfolded protein response (UPR). ER-PQC and the UPR in cardiac myocytes growing under physiological conditions, including normal development, exercise, and pregnancy, are sufficient to support hypertrophic growth of each cardiac myocyte. However, the ER-PQC and UPR are insufficient to respond to the challenge of cardiac myocyte growth under pathological conditions, including myocardial infarction and heart failure. In part, this insufficiency is due to a continual decline in the expression levels of important adaptive UPR components as a function of age and during myocardial pathology. This chapter will discuss the physiological and pathological conditions unique to the heart that involves ER-PQC, and whether the UPR is adaptive or maladaptive under these circumstances.},
	article-doi = {10.1007/82\_2017\_54},
	author = {Arrieta, A. and Blackwood, E. A. and Glembotski, C. C.},
	completed = {20180920},
	electronic-issn = {2196-9965},
	grantno = {R01 HL135893/HL/NHLBI NIH HHS/United States},
	history = {2017/10/14 06:00 [entrez]},
	journal = {Current topics in microbiology and immunology},
	keywords = {Activating Transcription Factor 6/physiology, Animals, Endoplasmic Reticulum/*metabolism, Humans, Myocardium/*metabolism, Myocytes, Cardiac/metabolism, Proteins/*metabolism, Unfolded Protein Response/*physiology, eIF-2 Kinase/physiology},
	language = {eng},
	linking-issn = {0070-217X},
	location-id = {10.1007/82\_2017\_54 [doi]},
	manuscript-id = {NIHMS949659},
	nlm-unique-id = {0110513},
	owner = {NLM},
	pages = {193--213},
	print-issn = {0070-217X},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (eIF-2 Kinase)},
	revised = {20200225},
	source = {Curr Top Microbiol Immunol. 2018;414:193-213. doi: 10.1007/82\_2017\_54.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {ER Protein Quality Control and the Unfolded Protein Response in the Heart.},
	title-abbreviation = {Curr Top Microbiol Immunol},
	volume = {414},
	year = {2018}
}

@article{Sacchi_2017_JournaloftheAmericanHeartAssociation_6_,
	abstract = {BACKGROUND: Aberrant Ca(2+) handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca(2+) handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl-prolyl cis-trans isomerase peptidyl-prolyl isomerase 1 (Pin1) is a critical mediator of myocardial hypertrophy development and cardiac progenitor cell cycle. However, the influence of Pin1 on calcium cycling regulation has not been explored. On the basis of these findings, the aim of this study is to define Pin1 as a novel modulator of Ca(2+) handling, with implications for improving myocardial contractility and potential for ameliorating development of heart failure. METHODS AND RESULTS: Pin1 gene deletion or pharmacological inhibition delays cytosolic Ca(2+) decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) and Na(2+)/Ca(2+) exchanger 1 protein levels. However, SERCA2a ATPase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1-deficient hearts, suggesting that Pin1 influences SERCA2a function. SERCA2a and Na(2+)/Ca(2+) exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca(2+) handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA2a and Na(2+)/Ca(2+) exchanger 1 proteins. CONCLUSIONS: Pin1 serves as a modulator of SERCA2a and Na(2+)/Ca(2+) exchanger 1 Ca(2+) handling proteins, with loss of function resulting in impaired cardiomyocyte relaxation, setting the stage for subsequent investigations to assess Pin1 dysregulation and modulation in the progression of heart failure.},
	article-doi = {10.1161/JAHA.117.006837},
	article-pii = {JAH32561},
	author = {Sacchi, Veronica and Wang, Bingyan J. and Kubli, Dieter and Martinez, Alexander S. and Jin, Jung-Kang and Alvarez, Roberto Jr and Hariharan, Nirmala and Glembotski, Christopher and Uchida, Takafumi and Malter, James S. and Yang, Yijun and Gross, Polina and Zhang, Chen and Houser, Steven and Rota, Marcello and Sussman, Mark A.},
	completed = {20180604},
	electronic-issn = {2047-9980},
	electronic-publication = {20171010},
	grantno = {R01 HL135893/HL/NHLBI NIH HHS/United States},
	history = {2018/06/05 06:00 [medline]},
	issue = {10},
	journal = {Journal of the American Heart Association},
	keywords = {Animals, Calcium/*metabolism, *Calcium Signaling, Heart Failure/*enzymology/genetics/physiopathology, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, Myocytes, Cardiac/*enzymology, NIMA-Interacting Peptidylprolyl Isomerase/deficiency/genetics/*metabolism, Protein Binding, Sarcoplasmic Reticulum/*enzymology, Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism, Sodium-Calcium Exchanger/*metabolism, Time Factors, Na+/Ca2+ exchange, cardiomyocyte, peptidyl‐prolyl isomerase 1, sarcoplasmic reticulum Ca2+‐ATPase},
	language = {eng},
	linking-issn = {2047-9980},
	location-id = {e006837},
	month = {Oct},
	nlm-unique-id = {101580524},
	owner = {NLM},
	publication-status = {epublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20190412},
	source = {J Am Heart Assoc. 2017 Oct 10;6(10):e006837. doi: 10.1161/JAHA.117.006837.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Peptidyl-Prolyl Isomerase 1 Regulates Ca(2+) Handling by Modulating Sarco(Endo)Plasmic Reticulum Calcium ATPase and Na(2+)/Ca(2+) Exchanger 1 Protein Levels and Function.},
	title-abbreviation = {J Am Heart Assoc},
	volume = {6},
	year = {2017}
}

@article{Glembotski_2017_CircRes_120_772,
	abstract = {Recent interest in mechanisms of stem cell-mediated repair in the heart have spawned the ``paracrine hypothesis'', which posits that stem cells release beneficial substances that improve regeneration and function of the injured and diseased myocardium. In support of this hypothesis are findings that small membranous vesicles called exosomes are released from stem cells and deliver beneficial cargo to cells in the heart. However, in addition to exosomes, which are released by the unconventional secretory pathway, are many other factors released by the unconventional and the conventional secretory pathways. A broader perspective of mechanisms of secretion, as well as an appreciation for the ways in which the secretion of a wide range of different types of molecules can be regulated, will spawn new avenues of thought necessary to move us beyond the exosome-centric view that drives much of the current thinking of the paracrine hypothesis of stem cell-mediated repair in the heart.},
	article-doi = {10.1161/CIRCRESAHA.116.310298},
	article-pii = {CIRCRESAHA.116.310298},
	author = {Glembotski, Christopher C.},
	completed = {20190226},
	electronic-issn = {1524-4571},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2019/02/27 06:00 [medline]},
	issue = {5},
	journal = {Circulation research},
	keywords = {Adult Stem Cells/*metabolism, Animals, Collagen/metabolism, Cytosol/metabolism, Exosomes/physiology, Fibroblasts/metabolism, Golgi Apparatus/metabolism, Heart/*physiology, Humans, Intercellular Signaling Peptides and Proteins/metabolism, Intracellular Signaling Peptides and Proteins/metabolism, Models, Biological, Myocardium/metabolism/pathology, Myocytes, Cardiac/metabolism, Paracrine Communication/*physiology, Regeneration/*physiology, *conventional, *exosomes, *heart, *secretion, *stem cells, *unconventional},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.116.310298 [doi]},
	manuscript-id = {NIHMS840685},
	month = {Mar},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {772--774},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {9007-34-5 (Collagen)},
	revised = {20190226},
	source = {Circ Res. 2017 Mar 3;120(5):772-774. doi: 10.1161/CIRCRESAHA.116.310298.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Expanding the Paracrine Hypothesis of Stem Cell-Mediated Repair in the Heart: When the Unconventional Becomes Conventional.},
	title-abbreviation = {Circ Res},
	volume = {120},
	year = {2017}
}

@article{Gray_2017_JMolCellCardiol_103_48,
	abstract = {Deletion of Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIδ isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIδ gene deletion. In this study we sought to compare the roles of the CaMKIIδ(B) and CaMKIIδ(C) subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIδKO, and mice expressing only CaMKIIδ(B) or δ(C) were subjected to ex vivo global ischemia for 25min followed by reperfusion. Infarct formation was assessed at 60min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKIIδ conferred significant protection from ex vivo I/R. Re-expression of CaMKIIδ(C) in the CaMKIIδKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIδ(B) was protective. Selective activation of CaMKIIδ(C) in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and tumor necrosis factor alpha (TNF-α) expression by CaMKIIδ(B) and CaMKIIδ(C). Selective activation of CaMKIIδ(C) was also observed and associated with NF-κB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-κB or TNF-α significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIδ(C), demonstrating distinct roles for CaMKIIδ subtypes in I/R and implicating acute activation of CaMKIIδ(C) and NF-κB in the pathogenesis of reperfusion injury.},
	article-doi = {10.1016/j.yjmcc.2017.01.002},
	article-pii = {S0022-2828(17)30002-0},
	author = {Gray, Charles B. B. and Suetomi, Takeshi and Xiang, Sunny and Mishra, Shikha and Blackwood, Erik A. and Glembotski, Christopher C. and Miyamoto, Shigeki and Westenbrink, B. Daan and Brown, Joan Heller},
	completed = {20170531},
	electronic-issn = {1095-8584},
	electronic-publication = {20170107},
	grantno = {R01 HL105242/HL/NHLBI NIH HHS/United States},
	history = {2017/01/13 06:00 [entrez]},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Biopsy, Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/*metabolism, Disease Models, Animal, Echocardiography, Gene Knockout Techniques, Mice, Mice, Transgenic, Myocardial Infarction/diagnosis/etiology/*metabolism/mortality, Myocardial Reperfusion Injury/diagnosis/genetics/*metabolism/mortality, Myocardium/metabolism/pathology, Myocytes, Cardiac/metabolism, NF-kappa B/metabolism, Phosphorylation, Rats, Signal Transduction, Tumor Necrosis Factor-alpha/metabolism, Ventricular Dysfunction, *CaMKII, *Heart, *Inflammation, *Ischemia/reperfusion, *Myocardial Infarction, *NF-κB, *Signal transduction, *TNF-α},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2017.01.002 [doi]},
	manuscript-id = {NIHMS878037},
	month = {Feb},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {48--55},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2017 Feb;103:48-55. doi: 10.1016/j.yjmcc.2017.01.002. Epub 2017 Jan 7.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {103},
	year = {2017}
}

@article{Jin_2017_CircRes_120_862,
	abstract = {RATIONALE: Endoplasmic reticulum (ER) stress causes the accumulation of misfolded proteins in the ER, activating the transcription factor, ATF6 (activating transcription factor 6 alpha), which induces ER stress response genes. Myocardial ischemia induces the ER stress response; however, neither the function of this response nor whether it is mediated by ATF6 is known. OBJECTIVE: Here, we examined the effects of blocking the ATF6-mediated ER stress response on ischemia/reperfusion (I/R) in cardiac myocytes and mouse hearts. METHODS AND RESULTS: Knockdown of ATF6 in cardiac myocytes subjected to I/R increased reactive oxygen species and necrotic cell death, both of which were mitigated by ATF6 overexpression. Under nonstressed conditions, wild-type and ATF6 knockout mouse hearts were similar. However, compared with wild-type, ATF6 knockout hearts showed increased damage and decreased function after I/R. Mechanistically, gene array analysis showed that ATF6, which is known to induce genes encoding ER proteins that augment ER protein folding, induced numerous oxidative stress response genes not previously known to be ATF6-inducible. Many of the proteins encoded by the ATF6-induced oxidative stress genes identified here reside outside the ER, including catalase, which is known to decrease damaging reactive oxygen species in the heart. Catalase was induced by the canonical ER stressor, tunicamycin, and by I/R in cardiac myocytes from wild-type but not in cardiac myocytes from ATF6 knockout mice. ER stress response elements were identified in the catalase gene and were shown to bind ATF6 in cardiac myocytes, which increased catalase promoter activity. Overexpression of catalase, in vivo, restored ATF6 knockout mouse heart function to wild-type levels in a mouse model of I/R, as did adeno-associated virus 9-mediated ATF6 overexpression. CONCLUSIONS: ATF6 serves an important role as a previously unappreciated link between the ER stress and oxidative stress gene programs, supporting a novel mechanism by which ATF6 decreases myocardial I/R damage.},
	article-doi = {10.1161/CIRCRESAHA.116.310266},
	article-pii = {CIRCRESAHA.116.310266},
	author = {Jin, Jung-Kang and Blackwood, Erik A. and Azizi, Khalid and Thuerauf, Donna J. and Fahem, Asal G. and Hofmann, Christoph and Kaufman, Randal J. and Doroudgar, Shirin and Glembotski, Christopher C.},
	comment = {Circ Res. 2017 Mar 3;120(5):759-761. PMID: 28254796},
	completed = {20170508},
	electronic-issn = {1524-4571},
	electronic-publication = {20161208},
	grantno = {R01 CA198103/CA/NCI NIH HHS/United States},
	history = {2016/12/10 06:00 [entrez]},
	issue = {5},
	journal = {Circulation research},
	keywords = {Activating Transcription Factor 6/*biosynthesis/deficiency, Animals, Animals, Newborn, Endoplasmic Reticulum Stress/*physiology, HEK293 Cells, HeLa Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Reperfusion Injury/*metabolism/pathology/prevention \& control, Myocardium/*metabolism/pathology, Myocytes, Cardiac, Oxidative Stress/*physiology, Rats, Rats, Sprague-Dawley, Signal Transduction/physiology, ATF6, cardiac myocyte, catalase, endoplasmic reticulum stress, ischemia, ischemia/reperfusion injury, oxidative stress, protein folding, unfolded protein response},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.116.310266 [doi]},
	manuscript-id = {NIHMS835441},
	month = {Mar},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {862--875},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {0 (Atf6 protein, mouse)},
	revised = {20181113},
	source = {Circ Res. 2017 Mar 3;120(5):862-875. doi: 10.1161/CIRCRESAHA.116.310266. Epub 2016 Dec 8.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart.},
	title-abbreviation = {Circ Res},
	volume = {120},
	year = {2017}
}

@article{Doroudgar_2016_JMolCellCardiol_100_54,
	abstract = {BACKGROUND: Myocardial infarction is followed by cardiac dysfunction, cellular death, and ventricular remodeling, including tissue fibrosis. S100A4 protein plays multiple roles in cellular survival, and tissue fibrosis, but the relative role of the S100A4 in the myocardium after myocardial infarction is unknown. This study aims to investigate the role of S100A4 in myocardial remodeling and cardiac function following infarct damage. METHODS AND RESULTS: S100A4 expression is low in the adult myocardium, but significantly increased following myocardial infarction. Deletion of S100A4 increased cardiac damage after myocardial infarction, whereas cardiac myocyte-specific overexpression of S100A4 protected the infarcted myocardium. Decreased cardiac function in S100A4 Knockout mice was accompanied with increased cardiac remodeling, fibrosis, and diminished capillary density in the remote myocardium. Loss of S100A4 caused increased apoptotic cell death both in vitro and in vivo in part mediated by decreased VEGF expression. Conversely, S100A4 overexpression protected cells against apoptosis in vitro and in vivo. Increased pro-survival AKT-signaling explained reduced apoptosis in S100A4 overexpressing cells. CONCLUSION: S100A4 expression protects cardiac myocytes against myocardial ischemia and is required for stabilization of cardiac function after MI.},
	article-doi = {10.1016/j.yjmcc.2016.10.001},
	article-pii = {S0022-2828(16)30377-7},
	author = {Doroudgar, Shirin and Quijada, Pearl and Konstandin, Mathias and Ilves, Kelli and Broughton, Kathleen and Khalafalla, Farid G. and Casillas, Alexandria and Nguyen, Kristine and Gude, Natalie and Toko, Haruhiro and Ornelas, Luis and Thuerauf, Donna J. and Glembotski, Christopher C. and Sussman, Mark A. and V{\"o}lkers, Mirko},
	completed = {20170531},
	electronic-issn = {1095-8584},
	electronic-publication = {20161006},
	grantno = {R21 HL102613/HL/NHLBI NIH HHS/United States},
	history = {2016/10/11 06:00 [entrez]},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Cell Death/genetics, Disease Models, Animal, Echocardiography, Gene Expression, Hemodynamics, Mice, Mice, Knockout, Myocardial Infarction/diagnosis/genetics/metabolism/physiopathology, Myocardial Ischemia/diagnosis/*genetics/*metabolism/physiopathology, Myocardium/*metabolism/pathology, S100 Calcium-Binding Protein A4/*genetics/metabolism, Stress, Physiological/*genetics, Ventricular Remodeling, *Myocardial infarction, *Remodeling, *S100A4},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2016.10.001 [doi]},
	manuscript-id = {NIHMS876822},
	month = {Nov},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {54--63},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {0 (S100 Calcium-Binding Protein A4)},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2016 Nov;100:54-63. doi: 10.1016/j.yjmcc.2016.10.001. Epub 2016 Oct 6.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {S100A4 protects the myocardium against ischemic stress.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {100},
	year = {2016}
}

@article{Reynolds_2016_IntJCardiol_225_371,
	abstract = {BACKGROUND: Junctophilin-2 (JPH2) is the primary structural protein for the coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes (JMCs) in cardiomyocytes. Effective signaling between these channels ensures adequate Ca-induced Ca release required for normal cardiac contractility. Disruption of JMC subcellular domains, a common feature of failing hearts, has been attributed to JPH2 downregulation. Here, we tested the hypothesis that adeno-associated virus type 9 (AAV9) mediated overexpression of JPH2 could halt the development of heart failure in a mouse model of transverse aortic constriction (TAC). METHODS AND RESULTS: Following TAC, a progressive decrease in ejection fraction was paralleled by a progressive decrease of cardiac JPH2 levels. AAV9-mediated expression of JPH2 rescued cardiac contractility in mice subjected to TAC. AAV9-JPH2 also preserved T-tubule structure. Moreover, the Ca(2+) spark frequency was reduced and the Ca(2+) transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca(2+) handling. CONCLUSIONS: This study demonstrates that AAV9-mediated JPH2 gene therapy maintained cardiac function in mice with early stage heart failure. Moreover, restoration of JPH2 levels prevented loss of T-tubules and suppressed abnormal SR Ca(2+) leak associated with contractile failure following TAC. These findings suggest that targeting JPH2 might be an attractive therapeutic approach for treating pathological cardiac remodeling during heart failure.},
	article-doi = {10.1016/j.ijcard.2016.10.021},
	article-pii = {S0167-5273(16)32855-8},
	author = {Reynolds, Julia O. and Quick, Ann P. and Wang, Qiongling and Beavers, David L. and Philippen, Leonne E. and Showell, Jordan and Barreto-Torres, Giselle and Thuerauf, Donna J. and Doroudgar, Shirin and Glembotski, Christopher C. and Wehrens, Xander H. T.},
	completed = {20171025},
	electronic-issn = {1874-1754},
	electronic-publication = {20161008},
	grantno = {R01 HL091947/HL/NHLBI NIH HHS/United States},
	history = {2016/10/21 06:00 [entrez]},
	journal = {International journal of cardiology},
	keywords = {Adenoviridae/genetics, Animals, Calcium Signaling/drug effects/*physiology, Cells, Cultured, Genetic Therapy/*methods, Genetic Vectors/administration \& dosage/genetics, Heart Failure/diagnostic imaging/*metabolism/*therapy, Male, Membrane Proteins/*biosynthesis/genetics, Mice, Mice, Inbred C57BL, Muscle Proteins/*biosynthesis/genetics, Myocytes, Cardiac/drug effects/metabolism, Ryanodine Receptor Calcium Release Channel/*physiology, Calcium, Cardiomyopathy, Gene therapy, Heart failure, Junctophilin, T-tubule},
	language = {eng},
	linking-issn = {0167-5273},
	location-id = {10.1016/j.ijcard.2016.10.021 [doi]},
	manuscript-id = {NIHMS823603},
	month = {Dec},
	nlm-unique-id = {8200291},
	owner = {NLM},
	pages = {371--380},
	print-issn = {0167-5273},
	publication-status = {ppublish},
	registry-number = {0 (ryanodine receptor 2. mouse)},
	revised = {20210112},
	source = {Int J Cardiol. 2016 Dec 15;225:371-380. doi: 10.1016/j.ijcard.2016.10.021. Epub 2016 Oct 8.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release.},
	title-abbreviation = {Int J Cardiol},
	volume = {225},
	year = {2016}
}

@article{Yu_2017_JCerebBloodFlowMetab_37_1069,
	abstract = {Impaired function of the endoplasmic reticulum (ER stress) is a hallmark of many human diseases including stroke. To restore ER function in stressed cells, the unfolded protein response (UPR) is induced, which activates 3 ER stress sensor proteins including activating transcription factor 6 (ATF6). ATF6 is then cleaved by proteases to form the short-form ATF6 (sATF6), a transcription factor. To determine the extent to which activation of the ATF6 UPR branch defines the fate and function of neurons after stroke, we generated a conditional and tamoxifen-inducible sATF6 knock-in mouse. To express sATF6 in forebrain neurons, we crossed our sATF6 knock-in mouse line with Emx1-Cre mice to generate ATF6-KI mice. After the ATF6 branch was activated in ATF6-KI mice with tamoxifen, mice were subjected to transient middle cerebral artery occlusion. Forced activation of the ATF6 UPR branch reduced infarct volume and improved functional outcome at 24\,h after stroke. Increased autophagic activity at early reperfusion time after stroke may contribute to the ATF6-mediated neuroprotection. We concluded that the ATF6 UPR branch is crucial to ischemic stroke outcome. Therefore, boosting UPR pro-survival pathways may be a promising therapeutic strategy for stroke.},
	article-doi = {10.1177/0271678X16650218},
	article-pii = {10.1177\_0271678X16650218},
	author = {Yu, Zhui and Sheng, Huaxin and Liu, Shuai and Zhao, Shengli and Glembotski, Christopher C. and Warner, David S. and Paschen, Wulf and Yang, Wei},
	completed = {20170818},
	electronic-issn = {1559-7016},
	electronic-publication = {20160720},
	grantno = {R03 NS078590/NS/NINDS NIH HHS/United States},
	history = {2016/05/25 06:00 [entrez]},
	issue = {3},
	journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism/pharmacology, Animals, Autophagy, Brain Infarction, Gene Knock-In Techniques, Infarction, Middle Cerebral Artery, Mice, Neurons/*metabolism, Neuroprotection/*drug effects, Recovery of Function, Stroke/*drug therapy, *Unfolded Protein Response, Brain ischemia, endoplasmic reticulum stress, neuroprotection, transgenic mice, unfolded protein response},
	language = {eng},
	linking-issn = {0271-678X},
	location-id = {10.1177/0271678X16650218 [doi]},
	month = {Mar},
	nlm-unique-id = {8112566},
	owner = {NLM},
	pages = {1069--1079},
	print-issn = {0271-678X},
	publication-status = {ppublish},
	registry-number = {0 (Atf6 protein, mouse)},
	revised = {20181113},
	source = {J Cereb Blood Flow Metab. 2017 Mar;37(3):1069-1079. doi: 10.1177/0271678X16650218. Epub 2016 Jul 20.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.},
	title-abbreviation = {J Cereb Blood Flow Metab},
	volume = {37},
	year = {2017}
}

@inproceedings{Glembotski_2015__117_914,
	article-doi = {10.1161/CIRCRESAHA.115.307644},
	article-pii = {CIRCRESAHA.115.307644},
	author = {Glembotski, Christopher C.},
	booktitle = {Circulation research},
	comment = {Circ Res. 2015 Nov 6;117(11):956-66. PMID: 26383969},
	completed = {20160219},
	electronic-issn = {1524-4571},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2016/02/20 06:00 [medline]},
	issue = {11},
	keywords = {Animals, Carrier Proteins/*metabolism, Cytosol/*metabolism, Female, Heart Diseases/*prevention \& control, Heart Ventricles/*metabolism, Male, Myocytes, Cardiac/*metabolism, *Signal Transduction, alpha-Crystallin B Chain/*metabolism, Editorials, proteasome endopeptidase complex, proteolysis, ubiquitination},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.115.307644 [doi]},
	manuscript-id = {NIHMS730250},
	month = {Nov},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {914--6},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {0 (alpha-Crystallin B Chain)},
	revised = {20181202},
	source = {Circ Res. 2015 Nov 6;117(11):914-6. doi: 10.1161/CIRCRESAHA.115.307644.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Breaking down the COP9 Signalsome in the heart: how inactivating a protein ubiquitin ligase increases protein ubiquitylation and protects the heart.},
	title-abbreviation = {Circ Res},
	volume = {117},
	year = {2015}
}

@article{Doroudgar_2015_CircRes_117_536,
	abstract = {RATIONALE: Hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (Hrd1) is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD has been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. OBJECTIVE: The objective of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. METHODS AND RESULTS: The effects of small interfering RNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure overload-induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin and tunicamycin increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, thapsigargin and tunicamycin dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction and increased apoptosis and cardiac hypertrophy, whereas Hrd1 overexpression preserved cardiac function and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure overload. CONCLUSIONS: Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy.},
	article-doi = {10.1161/CIRCRESAHA.115.306993},
	article-pii = {CIRCRESAHA.115.306993},
	author = {Doroudgar, Shirin and V{\"o}lkers, Mirko and Thuerauf, Donna J. and Khan, Mohsin and Mohsin, Sadia and Respress, Jonathan L. and Wang, Wei and Gude, Natalie and M{\"u}ller, Oliver J. and Wehrens, Xander H. T. and Sussman, Mark A. and Glembotski, Christopher C.},
	comment = {Circ Res. 2015 Aug 28;117(6):484-6. PMID: 26316602},
	completed = {20151116},
	electronic-issn = {1524-4571},
	electronic-publication = {20150702},
	grantno = {R01 HL117641/HL/NHLBI NIH HHS/United States},
	history = {2015/11/17 06:00 [medline]},
	issue = {6},
	journal = {Circulation research},
	keywords = {Adaptation, Physiological/*physiology, Animals, Animals, Newborn, Cells, Cultured, Endoplasmic Reticulum/metabolism, Endoplasmic Reticulum Stress/*physiology, Endoplasmic Reticulum-Associated Degradation/*physiology, Gene Knockdown Techniques, Mice, Myocytes, Cardiac/*metabolism, Rats, Rats, Sprague-Dawley, Ubiquitin-Protein Ligases/*biosynthesis, cardiac, endoplasmic reticulum stress, hydroxymethylglutaryl CoA reductases, myocytes, protein folding, proteolysis},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.115.306993 [doi]},
	manuscript-id = {NIHMS704862},
	month = {Aug},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {536--46},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 2.3.2.27 (Ubiquitin-Protein Ligases)},
	revised = {20181113},
	source = {Circ Res. 2015 Aug 28;117(6):536-46. doi: 10.1161/CIRCRESAHA.115.306993. Epub 2015 Jul 2.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes.},
	title-abbreviation = {Circ Res},
	volume = {117},
	year = {2015}
}

@article{Glembotski_2014_CircRes_115_546,
	abstract = {The ER stress-inducible transcription factor, x-box binding protein 1 (XBP1), which enhances protein glycosylation in the endoplasmic reticulum (ER), was shown to also enhance protein glycosylation outside the ER, via a process called O-GlcNAcylation, which protected the heart from ischemia/reperfusion damage.},
	article-doi = {10.1161/CIRCRESAHA.114.304855},
	article-pii = {CIRCRESAHA.114.304855},
	author = {Glembotski, Christopher C.},
	comment = {Cell. 2014 Mar 13;156(6):1179-92. PMID: 24630721},
	completed = {20141107},
	electronic-issn = {1524-4571},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2014/11/08 06:00 [medline]},
	issue = {6},
	journal = {Circulation research},
	keywords = {Animals, *Biosynthetic Pathways, DNA-Binding Proteins/*metabolism, Hexosamines/*metabolism, Humans, Male, Transcription Factors/*metabolism, *Unfolded Protein Response},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.114.304855 [doi]},
	manuscript-id = {NIHMS617438},
	month = {Aug},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {546--8},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {0 (Transcription Factors)},
	revised = {20181202},
	source = {Circ Res. 2014 Aug 29;115(6):546-8. doi: 10.1161/CIRCRESAHA.114.304855.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Finding the missing link between the unfolded protein response and O-GlcNAcylation in the heart.},
	title-abbreviation = {Circ Res},
	volume = {115},
	year = {2014}
}

@article{Volkers_2014_EMBOmolecularmedicine_6_57,
	abstract = {Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases.},
	article-doi = {10.1002/emmm.201303183},
	article-pii = {emmm.201303183},
	author = {V{\"o}lkers, Mirko and Doroudgar, Shirin and Nguyen, Nathalie and Konstandin, Mathias H. and Quijada, Pearl and Din, Shabana and Ornelas, Luis and Thuerauf, Donna J. and Gude, Natalie and Friedrich, Kilian and Herzig, Stephan and Glembotski, Christopher C. and Sussman, Mark A.},
	completed = {20140725},
	electronic-issn = {1757-4684},
	grantno = {R01 HL105759-03/HL/NHLBI NIH HHS/United States},
	history = {2014/07/26 06:00 [medline]},
	issue = {1},
	journal = {EMBO molecular medicine},
	keywords = {Adenoviridae/genetics, Animals, Cells, Cultured, Diabetes Mellitus, Experimental/complications/metabolism, Diabetic Cardiomyopathies/etiology/*prevention \& control, Diet, High-Fat, Genetic Vectors/metabolism, Insulin/*metabolism, Male, Mechanistic Target of Rapamycin Complex 1, Metabolome, Mice, Mice, Inbred C57BL, Mice, Obese, Multiprotein Complexes/antagonists \& inhibitors/metabolism, Myocytes, Cardiac/cytology/*metabolism, Obesity/complications/metabolism, Phenotype, Phosphoproteins/genetics/*metabolism, TOR Serine-Threonine Kinases/antagonists \& inhibitors/metabolism},
	language = {eng},
	linking-issn = {1757-4676},
	location-id = {10.1002/emmm.201303183 [doi]},
	month = {Jan},
	nlm-unique-id = {101487380},
	owner = {NLM},
	pages = {57--65},
	print-issn = {1757-4676},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)},
	revised = {20181113},
	source = {EMBO Mol Med. 2014 Jan;6(1):57-65. doi: 10.1002/emmm.201303183.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity.},
	title-abbreviation = {EMBO Mol Med},
	volume = {6},
	year = {2014}
}

@article{Glembotski_2013_CircRes_113_1112,
	article-doi = {10.1161/CIRCRESAHA.113.302490},
	article-pii = {CIRCRESAHA.113.302490},
	author = {Glembotski, Christopher C.},
	completed = {20140214},
	electronic-issn = {1524-4571},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2014/02/15 06:00 [medline]},
	issue = {10},
	journal = {Circulation research},
	keywords = {Animals, Autobiographies as Topic, Catecholamines/physiology, Cell Differentiation/physiology, Cell Proliferation, Cells, Cultured, *Disease Models, Animal, History, 20th Century, History, 21st Century, Hypertrophy/pathology/physiopathology, Myocytes, Cardiac/*pathology/*physiology, Rats, Receptors, Adrenergic/physiology, adrenergic agents, alpha1-adrenergic receptor, cultured cardiac myocytes, heart failure, hypertrophy, muscle cells},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.113.302490 [doi]},
	manuscript-id = {NIHMS674012},
	month = {Oct},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1112--6},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {0 (Receptors, Adrenergic)},
	revised = {20191210},
	source = {Circ Res. 2013 Oct 25;113(10):1112-6. doi: 10.1161/CIRCRESAHA.113.302490.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Classic studies of cultured cardiac myocyte hypertrophy: interview with a transformer.},
	title-abbreviation = {Circ Res},
	volume = {113},
	year = {2013}
}

@article{Glembotski_2014_JMolCellCardiol_71_11,
	abstract = {The hypertrophic growth of cardiac myocytes is a highly dynamic process that underlies physiological and pathological adaptation of the heart. Accordingly, a better understanding of the molecular underpinnings of cardiac myocyte hypertrophy is required in order to fully appreciate the causes and functional consequences of the changes in the size of the healthy and diseased heart. Hypertrophy is driven by increases in cardiac myocyte protein, which must be balanced by cellular ability to maintain protein quality in order to avoid maladaptive accumulation of toxic misfolded proteins. Recent studies have shown that the endoplasmic reticulum (ER), which, in cardiac myocytes, comprises the sarco/endoplasmic reticulum (SR/ER), is the site of most protein synthesis. Thus, the protein quality control machinery located at the SR/ER is likely to be an important determinant of whether the heart responds adaptively to hypertrophic growth stimuli. The SR/ER-transmembrane protein, ATF6, serves a critical protein quality control function as a first responder to the accumulation of potentially toxic, misfolded proteins. Misfolded proteins transform ATF6 into a transcription factor that regulates a gene program that is partly responsible for enhancing protein quality control. Two ATF6-inducible genes that have been studied in the heart and shown to be adaptive are RCAN1 and Derl3, which encode proteins that decrease protein-folding demand, and enhance degradation of misfolded proteins, respectively. Thus, the ATF6-regulated SR/ER protein quality control system is important for maintaining protein quality during growth, making ATF6, and other components of the system, potentially attractive targets for the therapeutic management pathological cardiac hypertrophy. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".},
	article-doi = {10.1016/j.yjmcc.2013.09.018},
	article-pii = {S0022-2828(13)00291-5},
	author = {Glembotski, Christopher C.},
	completed = {20150212},
	electronic-issn = {1095-8584},
	electronic-publication = {20131016},
	grantno = {R01 NS025037/NS/NINDS NIH HHS/United States},
	history = {2015/02/13 06:00 [medline]},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Activating Transcription Factor 6/*metabolism, Animals, Endoplasmic Reticulum/*metabolism, Heart/*physiology, Humans, Muscle Proteins/*biosynthesis, Myocytes, Cardiac/*metabolism, Protein Biosynthesis, Protein Folding, Transcription Factors/metabolism, Ubiquitin/metabolism, ATF6, Cardiac hypertrophy, Cardiac myocyte, Endoplasmic reticulum, Protein quality control, Sarcoplasmic reticulum},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2013.09.018 [doi]},
	manuscript-id = {NIHMS622023},
	month = {Jun},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {11--5},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {0 (Ubiquitin)},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2014 Jun;71:11-5. doi: 10.1016/j.yjmcc.2013.09.018. Epub 2013 Oct 16.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Roles for ATF6 and the sarco/endoplasmic reticulum protein quality control system in the heart.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {71},
	year = {2014}
}

@article{Volkers_2013_Circulation_128_2132,
	abstract = {BACKGROUND: The mechanistic target of rapamycin (mTOR) comprises 2 structurally distinct multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and mTORC2). Deregulation of mTOR signaling occurs during and contributes to the severity of myocardial damage from ischemic heart disease. However, the relative roles of mTORC1 versus mTORC2 in the pathogenesis of ischemic damage are unknown. METHODS AND RESULTS: Combined pharmacological and molecular approaches were used to alter the balance of mTORC1 and mTORC2 signaling in cultured cardiac myocytes and in mouse hearts subjected to conditions that mimic ischemic heart disease. The importance of mTOR signaling in cardiac protection was demonstrated by pharmacological inhibition of both mTORC1 and mTORC2 with Torin1, which led to increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. Predominant mTORC1 signaling mediated by suppression of mTORC2 with Rictor similarly increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. In comparison, preferentially shifting toward mTORC2 signaling by inhibition of mTORC1 with PRAS40 led to decreased cardiomyocyte apoptosis and tissue damage after myocardial infarction. CONCLUSIONS: These results suggest that selectively increasing mTORC2 while concurrently inhibiting mTORC1 signaling is a novel therapeutic approach for the treatment of ischemic heart disease.},
	article-doi = {10.1161/CIRCULATIONAHA.113.003638},
	article-pii = {CIRCULATIONAHA.113.003638},
	author = {V{\"o}lkers, Mirko and Konstandin, Mathias H. and Doroudgar, Shirin and Toko, Haruhiro and Quijada, Pearl and Din, Shabana and Joyo, Anya and Ornelas, Luis and Samse, Kaitleen and Thuerauf, Donna J. and Gude, Natalie and Glembotski, Christopher C. and Sussman, Mark A.},
	completed = {20140128},
	electronic-issn = {1524-4539},
	electronic-publication = {20130905},
	grantno = {R01 HL105759-03/HL/NHLBI NIH HHS/United States},
	history = {2014/01/29 06:00 [medline]},
	issue = {19},
	journal = {Circulation},
	keywords = {Adaptor Proteins, Signal Transducing/genetics/metabolism, Animals, Apoptosis/physiology, Carrier Proteins/metabolism, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes/*antagonists \& inhibitors/genetics/*metabolism, Myocardial Infarction/*metabolism/pathology, Myocardial Ischemia/*metabolism/pathology, Myocytes, Cardiac/cytology/physiology, Naphthyridines/pharmacology, Primary Cell Culture, Rapamycin-Insensitive Companion of mTOR Protein, Recombinant Proteins/genetics/metabolism, Signal Transduction/drug effects/*physiology, TOR Serine-Threonine Kinases/*antagonists \& inhibitors/genetics/*metabolism, AKT1S1 protein, human, RICTOR protein, human, TOR serine-threonine kinases},
	language = {eng},
	linking-issn = {0009-7322},
	location-id = {10.1161/CIRCULATIONAHA.113.003638 [doi]},
	manuscript-id = {NIHMS600045},
	month = {Nov},
	nlm-unique-id = {0147763},
	owner = {NLM},
	pages = {2132--44},
	print-issn = {0009-7322},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)},
	revised = {20181113},
	source = {Circulation. 2013 Nov 5;128(19):2132-44. doi: 10.1161/CIRCULATIONAHA.113.003638. Epub 2013 Sep 5.},
	status = {MEDLINE},
	subset = {IM},
	termowner = {NOTNLM},
	timestamp = {2021.09.20},
	title = {Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage.},
	title-abbreviation = {Circulation},
	volume = {128},
	year = {2013}
}

@article{Volkers_2013_PNAS_110_12661,
	abstract = {Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40.},
	article-doi = {10.1073/pnas.1301455110},
	article-pii = {201301455},
	author = {V{\"o}lkers, Mirko and Toko, Haruhiro and Doroudgar, Shirin and Din, Shabana and Quijada, Pearl and Joyo, Anya Y. and Ornelas, Luis and Joyo, Eri and Thuerauf, Donna J. and Konstandin, Mathias H. and Gude, Natalie and Glembotski, Christopher C. and Sussman, Mark A.},
	completed = {20131126},
	electronic-issn = {1091-6490},
	electronic-publication = {20130710},
	grantno = {R01 HL117163/HL/NHLBI NIH HHS/United States},
	history = {2013/12/16 06:00 [medline]},
	issue = {31},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	keywords = {Animals, Cardiomegaly/genetics/*metabolism/pathology/therapy, Male, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes/genetics/*metabolism, Muscle Proteins/genetics/*metabolism, Mutation, Myocytes, Cardiac/*metabolism/pathology, Phosphoproteins/genetics/*metabolism, Phosphorylation/genetics, Proto-Oncogene Proteins c-akt/genetics/metabolism, *Signal Transduction, TOR Serine-Threonine Kinases/genetics/*metabolism},
	language = {eng},
	linking-issn = {0027-8424},
	location-id = {10.1073/pnas.1301455110 [doi]},
	month = {Jul},
	nlm-unique-id = {7505876},
	owner = {NLM},
	pages = {12661--6},
	print-issn = {0027-8424},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)},
	revised = {20181113},
	source = {Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12661-6. doi: 10.1073/pnas.1301455110. Epub 2013 Jul 10.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1.},
	title-abbreviation = {Proc Natl Acad Sci U S A},
	volume = {110},
	year = {2013}
}

@article{Toko_2013_CircRes_112_1244,
	abstract = {RATIONALE: Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown. OBJECTIVE: To establish the role of Pin1 in the heart. METHODS AND RESULTS: Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation. CONCLUSIONS: Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.},
	article-doi = {10.1161/CIRCRESAHA.113.301084},
	article-pii = {CIRCRESAHA.113.301084},
	author = {Toko, Haruhiro and Konstandin, Mathias H. and Doroudgar, Shirin and Ormachea, Lucia and Joyo, Eri and Joyo, Anya Y. and Din, Shabana and Gude, Natalie A. and Collins, Brett and V{\"o}lkers, Mirko and Thuerauf, Donna J. and Glembotski, Christopher C. and Chen, Chun-Hau and Lu, Kun Ping and M{\"u}ller, Oliver J. and Uchida, Takafumi and Sussman, Mark A.},
	completed = {20130620},
	electronic-issn = {1524-4571},
	electronic-publication = {20130313},
	grantno = {R01 HL117163/HL/NHLBI NIH HHS/United States},
	history = {2013/06/21 06:00 [medline]},
	issue = {9},
	journal = {Circulation research},
	keywords = {Animals, Cardiomegaly/diagnostic imaging/*enzymology/pathology/physiopathology/prevention \& control, Dependovirus/genetics, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases/metabolism, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases/metabolism, Myocytes, Cardiac/*enzymology/pathology, NIMA-Interacting Peptidylprolyl Isomerase, Peptidylprolyl Isomerase/deficiency/genetics/*metabolism, Proto-Oncogene Proteins c-akt/metabolism, RNA Interference, Rats, *Signal Transduction, Time Factors, Transduction, Genetic, Transfection, Ultrasonography, raf Kinases/metabolism},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.113.301084 [doi]},
	manuscript-id = {NIHMS467857},
	month = {Apr},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1244--52},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 5.2.1.8 (Pin1 protein, mouse)},
	revised = {20181113},
	source = {Circ Res. 2013 Apr 26;112(9):1244-52. doi: 10.1161/CIRCRESAHA.113.301084. Epub 2013 Mar 13.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1.},
	title-abbreviation = {Circ Res},
	volume = {112},
	year = {2013}
}

@article{Doroudgar_2013_CircRes_112_9,
	abstract = {Thrombospondins are secreted, extracellular matrix (ECM) proteins that are upregulated in the heart and other tissues in response to ischemic injury and myocardial stress. Roles for thrombospondins after they are secreted have been examined in a variety of disease models, including myocardial pathology. However, a recent study published in the journal Cell by Lynch et al shifts this paradigm by focusing on roles for intracellular thrombospondins; these authors showed that thrombospondin-4 (Thbs4) can function from within cells to protect the heart by enhancing adaptive aspects of the endoplasmic reticulum (ER) stress response that are mediated by activating transcription factor 6, ATF6. Although this study was carried out in the cardiac context, the results add to our understanding of protein folding and quality control in all tissues. Moreover, the findings underscore the potential widespread therapeutic benefit of enhancing adaptive responses that are regulated by ATF6.},
	article-doi = {10.1161/CIRCRESAHA.112.280560},
	article-pii = {112/1/9},
	author = {Doroudgar, Shirin and Glembotski, Christopher C.},
	comment = {Circ Res. 2013 Feb 1;112(3):e31 Cell. 2012 Jun 8;149(6):1257-68. PMID: 22682248},
	completed = {20130227},
	electronic-issn = {1524-4571},
	grantno = {HL-075573/HL/NHLBI NIH HHS/United States},
	history = {2013/01/05 06:01 [medline]},
	issue = {1},
	journal = {Circulation research},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.112.280560 [doi]},
	manuscript-id = {NIHMS432281},
	month = {Jan},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {9--12},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	revised = {20181113},
	source = {Circ Res. 2013 Jan 4;112(1):9-12. doi: 10.1161/CIRCRESAHA.112.280560.},
	status = {PubMed-not-MEDLINE},
	timestamp = {2021.09.20},
	title = {ATF6 [corrected] and thrombospondin 4: the dynamic duo of the adaptive endoplasmic reticulum stress response.},
	title-abbreviation = {Circ Res},
	volume = {112},
	year = {2013}
}

@article{Glembotski_2012_PhysiologyBethesda_27_343,
	abstract = {Although the function of the sarcoplasmic/endoplasmic reticulum (SR/ER) in cardiac contractile calcium handling is well established, its roles in protein synthesis, folding, and quality control in cardiac myocytes are not as clear. This review explores evidence suggesting that, in cardiac myocytes, protein synthesis and contractile calcium handling may be physically and functionally integrated.},
	address = {United States},
	article-doi = {10.1152/physiol.00034.2012},
	article-pii = {27/6/343},
	author = {Glembotski, Christopher C.},
	completed = {20131107},
	electronic-issn = {1548-9221},
	grantno = {P01 HL-085577/HL/NHLBI NIH HHS/United States},
	history = {2013/11/08 06:00 [medline]},
	issue = {6},
	journal = {Physiology (Bethesda, Md.)},
	keywords = {Animals, Endoplasmic Reticulum/*physiology, Humans, Myocardial Contraction/*physiology, Myocytes, Cardiac/*physiology, *Protein Biosynthesis, Quality Control, Sarcoplasmic Reticulum/*physiology},
	language = {eng},
	linking-issn = {1548-9221},
	location-id = {10.1152/physiol.00034.2012 [doi]},
	month = {Dec},
	nlm-unique-id = {101208185},
	owner = {NLM},
	pages = {343--50},
	publication-status = {ppublish},
	revised = {20161019},
	source = {Physiology (Bethesda). 2012 Dec;27(6):343-50. doi: 10.1152/physiol.00034.2012.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Roles for the sarco-/endoplasmic reticulum in cardiac myocyte contraction, protein synthesis, and protein quality control.},
	title-abbreviation = {Physiology (Bethesda)},
	volume = {27},
	year = {2012}
}

@article{Doroudgar_2013_JMolCellCardiol_55_85,
	abstract = {Secreted and membrane proteins play critical roles in myocardial health and disease. Studies in non-myocytes have shown that the peri-nuclear ER is the site for synthesis, folding, and quality control of most secreted and membrane proteins, as well as a nexus of a signal transduction system, called the ER stress response, which informs the cell about the status of ER protein folding. Moreover, the dynamic physical and functional association of the ER with mitochondria is a key site responsible for integrating ER function and mitochondrial metabolism, but is only just beginning to be understood in the myocardium. Although a great deal is known about roles played by the sarcoplasmic reticulum (SR) in contractile calcium handling in the heart, little is known about the relative locations and functions of the peri-nuclear ER and the SR in terms of secreted and membrane protein synthesis and folding. In this review we will explore the current state of knowledge of the location of secreted and membrane protein synthesis, folding, and quality control machinery in cardiac myocytes, as well as our understanding of the functional consequences of ER stress and the unfolded protein response in the heart in terms of protein synthesis, cell growth, and metabolic regulation. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".},
	article-doi = {10.1016/j.yjmcc.2012.10.006},
	article-pii = {S0022-2828(12)00374-4},
	author = {Doroudgar, Shirin and Glembotski, Christopher C.},
	completed = {20130703},
	electronic-issn = {1095-8584},
	electronic-publication = {20121023},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2013/07/05 06:00 [medline]},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Endoplasmic Reticulum/*metabolism, Endoplasmic Reticulum Stress, Heart/*physiology, Humans, Myocardium/*metabolism, Protein Biosynthesis, Sarcoplasmic Reticulum/metabolism, Signal Transduction},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2012.10.006 [doi]},
	manuscript-id = {NIHMS421540},
	month = {Feb},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {85--91},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2013 Feb;55:85-91. doi: 10.1016/j.yjmcc.2012.10.006. Epub 2012 Oct 23.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {New concepts of endoplasmic reticulum function in the heart: programmed to conserve.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {55},
	year = {2013}
}

@inproceedings{Glembotski_2012__111_509,
	article-doi = {10.1161/CIRCRESAHA.112.275917},
	article-pii = {111/5/509},
	author = {Glembotski, Christopher C.},
	booktitle = {Circulation research},
	comment = {Circ Res. 2012 Aug 17;111(5):532-42. PMID: 22740087},
	completed = {20121031},
	electronic-issn = {1524-4571},
	grantno = {R03 EB011698/EB/NIBIB NIH HHS/United States},
	history = {2012/11/01 06:00 [medline]},
	issue = {5},
	keywords = {Animals, Myocardial Reperfusion Injury/*genetics/*physiopathology, Myocytes, Cardiac/*physiology, Proteasome Endopeptidase Complex/*genetics/*metabolism},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.112.275917 [doi]},
	manuscript-id = {NIHMS401761},
	month = {Aug},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {509--12},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 3.4.25.1 (Proteasome Endopeptidase Complex)},
	revised = {20181201},
	source = {Circ Res. 2012 Aug 17;111(5):509-12. doi: 10.1161/CIRCRESAHA.112.275917.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Clarifying the cardiac proteasome paradox: protein quality control.},
	title-abbreviation = {Circ Res},
	volume = {111},
	year = {2012}
}

@article{Eletto_2012_JCellSci_125_4865,
	abstract = {ER stress leads to upregulation of multiple folding and quality control components, known as the unfolded protein response (UPR). Glucose Regulated Protein 78 (GRP78) (also known as binding immunoglobulin protein, BiP, and HSPA5) and GRP94 are often upregulated coordinately as part of this homeostatic response. Given that endoplasmic reticulum (ER) chaperones have distinct sets of clients, we asked how cells respond to ablation of individual chaperones. The cellular responses to silencing BiP, GRP94, HSP47, PDIA6 and OS-9, were distinct. When BiP was silenced, a widespread UPR was observed, but when GRP94 was either inhibited or depleted by RNA interference (RNAi), the expression of only some genes was induced, notably those encoding BiP and protein disulfide isomerase A6 (PDIA6). Silencing of HSP47 or OS-9 did not lead to any compensatory induction of other genes. The selective response to GRP94 depletion was distinct from a typical ER stress response, both because other UPR target genes were not affected and because the canonical UPR signaling branches were not activated. The response to silencing of GRP94 did not preclude further UPR induction when chemical stress was imposed. Importantly, re-expression of wild-type GRP94 in the silenced cells prevented the upregulation of BiP and PDIA6, whereas re-expression of an ATPase-deficient GRP94 mutant did not, indicating that cells monitor the activity state of GRP94. These findings suggest that cells are able to distinguish among folding resources and generate distinct responses.},
	article-doi = {10.1242/jcs.108928},
	article-pii = {jcs.108928},
	author = {Eletto, Davide and Maganty, Avinash and Eletto, Daniela and Dersh, Devin and Makarewich, Catherine and Biswas, Chhanda and Paton, James C. and Paton, Adrienne W. and Doroudgar, Shirin and Glembotski, Christopher C. and Argon, Yair},
	completed = {20130529},
	electronic-issn = {1477-9137},
	electronic-publication = {20120801},
	grantno = {EB011698/EB/NIBIB NIH HHS/United States},
	history = {2013/05/31 06:00 [medline]},
	issue = {Pt 20},
	journal = {Journal of cell science},
	keywords = {Animals, Endoplasmic Reticulum Stress/genetics, Gene Silencing, HeLa Cells, *Heat-Shock Proteins/genetics/metabolism, Humans, *Membrane Glycoproteins/genetics/metabolism, Mice, NIH 3T3 Cells, Protein Disulfide-Isomerases/genetics/metabolism, *Protein Folding, Signal Transduction, Unfolded Protein Response/*genetics},
	language = {eng},
	linking-issn = {0021-9533},
	location-id = {10.1242/jcs.108928 [doi]},
	month = {Oct},
	nlm-unique-id = {0052457},
	owner = {NLM},
	pages = {4865--75},
	print-issn = {0021-9533},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20181202},
	source = {J Cell Sci. 2012 Oct 15;125(Pt 20):4865-75. doi: 10.1242/jcs.108928. Epub 2012 Aug 1.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Limitation of individual folding resources in the ER leads to outcomes distinct from the unfolded protein response.},
	title-abbreviation = {J Cell Sci},
	volume = {125},
	year = {2012}
}

@article{Glembotski_2012_JBiolChem_287_25893,
	abstract = {The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to protect cells from stress-induced cell death before and after its secretion; however, the conditions under which it is secreted are not known. Accordingly, we examined the mechanism of MANF release from cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway. Although the secretion of proteins via the constitutive pathway is not known to increase upon changes in intracellular calcium, MANF secretion was increased within 30 min of treating cells with compounds that deplete sarcoplasmic reticulum (SR)/ER calcium. In contrast, secretion of atrial natriuretic factor from ventricular myocytes was not increased by SR/ER calcium depletion, suggesting that not all secreted proteins exhibit the same characteristics as MANF. We postulated that SR/ER calcium depletion triggered MANF secretion by decreasing its retention. Consistent with this were co-immunoprecipitation and live cell, zero distance, photo affinity cross-linking, demonstrating that, in part, MANF was retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, GRP78 (glucose-regulated protein 78 kDa). This unusual mechanism of regulating secretion from the constitutive secretory pathway provides a potentially missing link in the mechanism by which extracellular MANF protects cells from stresses that deplete SR/ER calcium. Consistent with this was our finding that administration of recombinant MANF to mice decreased tissue damage in an in vivo model of myocardial infarction, a condition during which ER calcium is known to be dysregulated, and MANF expression is induced.},
	article-doi = {10.1074/jbc.M112.356345},
	article-pii = {M112.356345},
	author = {Glembotski, Christopher C. and Thuerauf, Donna J. and Huang, Chengqun and Vekich, John A. and Gottlieb, Roberta A. and Doroudgar, Shirin},
	completed = {20121011},
	electronic-issn = {1083-351X},
	electronic-publication = {20120525},
	grantno = {R01 AG033283/AG/NIA NIH HHS/United States},
	history = {2012/10/12 06:00 [medline]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Calcium/*metabolism, Endoplasmic Reticulum Stress, HeLa Cells, Heat-Shock Proteins/metabolism, Humans, Male, Membrane Glycoproteins/metabolism, Mice, Myocardial Ischemia/*metabolism/pathology, Myocardial Reperfusion Injury/metabolism/pathology, Myocytes, Cardiac/metabolism, Nerve Growth Factors/*metabolism/physiology, Protein Binding, Protein Sorting Signals, Protein Structure, Tertiary, Proteins/*metabolism/physiology, Rats, Sarcoplasmic Reticulum/drug effects/*metabolism, Thapsigargin/pharmacology, Tunicamycin/pharmacology},
	language = {eng},
	linking-issn = {0021-9258},
	location-id = {10.1074/jbc.M112.356345 [doi]},
	month = {Jul},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {25893--904},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20210205},
	source = {J Biol Chem. 2012 Jul 27;287(31):25893-904. doi: 10.1074/jbc.M112.356345. Epub 2012 May 25.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion.},
	title-abbreviation = {J Biol Chem},
	volume = {287},
	year = {2012}
}

@article{Vekich_2012_JMolCellCardiol_53_259,
	abstract = {Proper folding of secreted and transmembrane proteins made in the rough endoplasmic reticulum (ER) requires oxygen for disulfide bond formation. Accordingly, ischemia can impair ER protein folding and initiate the ER stress response, which we previously showed is activated in the ischemic heart and in culture cardiac myocytes subjected to simulated ischemia. ER stress and ischemia activate the transcription factor, activating transcription factor 6 (ATF6), which induces numerous genes, many of which have not been identified, or examined in the heart. Using an ATF6 transgenic mouse model, we previously showed that ATF6 protected the heart from ischemic damage; however, the mechanism of this protection remains to be determined. In this study, we showed that, in the mouse heart, and in cultured cardiac myocytes, ATF6 induced the protein disulfide isomerase associated 6 (PDIA6) gene, which encodes an ER enzyme that catalyzes protein disulfide bond formation. Moreover, in cultured cardiac myocytes, ER stress-mediated PDIA6 promoter activation was ATF6-dependent, and required an ER stress response element (ERSE) and a nearby CCAAT box element. Electromobility shift assays and chromatin immunoprecipitation showed that ATF6 bound to the ERSE in the PDIA6 promoter, in vitro, and in the mouse heart, in vivo. Gain- and loss-of-function studies showed that PDIA6 protected cardiac myocytes against simulated ischemia/reperfusion-induced death in a manner that was dependent on the catalytic activity of PDIA6. Thus, by facilitating disulfide bond formation, and enhanced ER protein folding, PDIA6 may contribute to the protective effects of ATF6 in the ischemic mouse heart.},
	article-doi = {10.1016/j.yjmcc.2012.05.005},
	article-pii = {S0022-2828(12)00182-4},
	author = {Vekich, John A. and Belmont, Peter J. and Thuerauf, Donna J. and Glembotski, Christopher C.},
	completed = {20121031},
	electronic-issn = {1095-8584},
	electronic-publication = {20120517},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2012/11/01 06:00 [medline]},
	issue = {2},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Animals, Cell Death/genetics/*physiology, Chromatin Immunoprecipitation, Chromatography, Liquid, Electrophoretic Mobility Shift Assay, Endoplasmic Reticulum Stress/genetics/physiology, Immunoblotting, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs/genetics, Myocytes, Cardiac/*cytology/*metabolism, Protein Disulfide-Isomerases/genetics/*metabolism, Real-Time Polymerase Chain Reaction, Reperfusion Injury/*physiopathology, Tandem Mass Spectrometry},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2012.05.005 [doi]},
	manuscript-id = {NIHMS382620},
	month = {Aug},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {259--67},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {EC 5.3.4.1 (Protein Disulfide-Isomerases)},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2012 Aug;53(2):259-67. doi: 10.1016/j.yjmcc.2012.05.005. Epub 2012 May 17.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Protein disulfide isomerase-associated 6 is an ATF6-inducible ER stress response protein that protects cardiac myocytes from ischemia/reperfusion-mediated cell death.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {53},
	year = {2012}
}

@article{Belmont_2012_JMolCellCardiol_52_1176,
	abstract = {A nodal regulator of endoplasmic reticulum stress is the transcription factor, ATF6, which is activated by ischemia and protects the heart from ischemic damage, in vivo. To explore mechanisms of ATF6-mediated protection in the heart, a whole-genome microRNA (miRNA) array analysis of RNA from the hearts of ATF6 transgenic (TG) mice was performed. The array identified 13 ATF6-regulated miRNAs, eight of which were downregulated, suggesting that they could contribute to increasing levels of their mRNAs. The down-regulated miRNAs, including miR-455, were predicted to target 45 mRNAs that we had previously shown by microarray analysis to be up-regulated by ATF6 in the heart. One of the miR-455 targets was calreticulin (Calr), which is up-regulated in the pathologic heart, where it modulates hypertrophic growth, potentially reducing the impact of the pathology. To validate the effects of miR-455, we showed that Calr protein was increased by ATF6 in mouse hearts, in vivo. In cultured cardiac myocytes, treatment with the ER stressor, tunicamycin, or with adenovirus encoding activated ATF6 decreased miR-455 and increased Calr levels, consistent with the effects of ATF6 on miR-455 and Calr, in vivo. Moreover, transfection of cultured cardiac myocytes with a synthetic precursor, premiR-455, decreased Calr levels, while transfection with an antisense, antimiR-455, increased Calr levels. The results of this study suggest that ER stress can regulate gene expression via ATF6-mediated changes in micro-RNA levels. Moreover, these findings support the hypothesis that ATF6-mediated down-regulation of miR-455 augments Calr expression, which may contribute to the protective effects of ATF6 in the heart.},
	article-doi = {10.1016/j.yjmcc.2012.01.017},
	article-pii = {S0022-2828(12)00050-8},
	author = {Belmont, Peter J. and Chen, Wenqiong J. and Thuerauf, Donna J. and Glembotski, Christopher C.},
	completed = {20120807},
	electronic-issn = {1095-8584},
	electronic-publication = {20120201},
	grantno = {R01 HL113656/HL/NHLBI NIH HHS/United States},
	history = {2012/08/08 06:00 [medline]},
	issue = {5},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Animals, Calreticulin/genetics/metabolism, Cells, Cultured, *Endoplasmic Reticulum Stress, Gene Expression Profiling, Heat-Shock Proteins/metabolism, Male, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs/*genetics/metabolism, Myocardium/*metabolism, Oligonucleotide Array Sequence Analysis, Primary Cell Culture, *RNA Interference, Rats, Rats, Sprague-Dawley, Transcription, Genetic, Up-Regulation},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2012.01.017 [doi]},
	manuscript-id = {NIHMS360260},
	month = {May},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {1176--82},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20181201},
	source = {J Mol Cell Cardiol. 2012 May;52(5):1176-82. doi: 10.1016/j.yjmcc.2012.01.017. Epub 2012 Feb 1.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {52},
	year = {2012}
}

@article{Doroudgar_2011_TrendsMolMed_17_207,
	abstract = {Intercellular communication depends on many factors, including proteins released via the classical or non-classical secretory pathways, many of which must be properly folded to be functional. Owing to their adverse effects on the secretion machinery, stresses such as ischemia can impair the folding of secreted proteins. Paradoxically, cells rely on secreted proteins to mount a response designed to resist stress-induced damage. This review examines this paradox using proteins secreted from the heart, cardiokines, as examples, and focuses on how the ischemic heart maintains or even increases the release of select cardiokines that regulate important cellular processes in the heart, including excitation-contraction coupling, hypertrophic growth, myocardial remodeling and stem cell function, in ways that moderate ischemic damage and enhance cardiac repair.},
	article-doi = {10.1016/j.molmed.2010.12.003},
	article-pii = {S1471-4914(10)00189-9},
	author = {Doroudgar, Shirin and Glembotski, Christopher C.},
	completed = {20110801},
	electronic-issn = {1471-499X},
	electronic-publication = {20110201},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2011/08/02 06:00 [medline]},
	issue = {4},
	journal = {Trends in molecular medicine},
	keywords = {Animals, Cell Communication, Cells, Cultured, Heat-Shock Proteins/*metabolism, Humans, Ischemia/*pathology, Muscle Proteins/metabolism, Myocardium/*pathology, Protein Folding, *Secretory Pathway},
	language = {eng},
	linking-issn = {1471-4914},
	location-id = {10.1016/j.molmed.2010.12.003 [doi]},
	manuscript-id = {NIHMS260860},
	month = {Apr},
	nlm-unique-id = {100966035},
	owner = {NLM},
	pages = {207--14},
	print-issn = {1471-4914},
	publication-status = {ppublish},
	registry-number = {0 (Muscle Proteins)},
	revised = {20181201},
	source = {Trends Mol Med. 2011 Apr;17(4):207-14. doi: 10.1016/j.molmed.2010.12.003. Epub 2011 Feb 1.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The cardiokine story unfolds: ischemic stress-induced protein secretion in the heart.},
	title-abbreviation = {Trends Mol Med},
	volume = {17},
	year = {2011}
}

@article{Glembotski_2011_JMolCellCardiol_51_512,
	abstract = {We define cardiomyokines as heart-derived secreted proteins that affect cardiovascular function via autocrine, paracrine and/or endocrine mechanisms. The subject of this review is the cardiomyokine, mesencephalic astrocyte-derived neurotrophic factor (MANF). The expression of MANF is increased in the ischemic heart, in part, through activation of ER stress, a condition that drastically impairs the expression and secretion of most cardiomyokines. This novel function of MANF suggests that it may have important roles in the ER stressed, ischemic heart. Consistent with this are recent findings showing that MANF protects against ischemic damage, and that it is anti-hypertrophic. Accordingly, in light of its function as a potentially secreted cardiomyokine, MANF has translational potential as a novel therapy for ischemic heart disease. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."},
	article-doi = {10.1016/j.yjmcc.2010.10.008},
	article-pii = {S0022-2828(10)00387-1},
	author = {Glembotski, Christopher C.},
	completed = {20120106},
	electronic-issn = {1095-8584},
	electronic-publication = {20101021},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2012/01/10 06:00 [medline]},
	issue = {4},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Amino Acid Sequence, Animals, Cardiomegaly/drug therapy/*physiopathology, Endoplasmic Reticulum Stress, Gene Expression, Heart Failure/drug therapy/*physiopathology, Humans, Molecular Sequence Data, Molecular Targeted Therapy, Nerve Growth Factors/genetics/metabolism/*physiology, Translational Medical Research},
	language = {eng},
	linking-issn = {0022-2828},
	location-id = {10.1016/j.yjmcc.2010.10.008 [doi]},
	manuscript-id = {NIHMS468781},
	month = {Oct},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {512--7},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {0 (Nerve Growth Factors)},
	revised = {20181201},
	source = {J Mol Cell Cardiol. 2011 Oct;51(4):512-7. doi: 10.1016/j.yjmcc.2010.10.008. Epub 2010 Oct 21.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Functions for the cardiomyokine, MANF, in cardioprotection, hypertrophy and heart failure.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {51},
	year = {2011}
}

@article{Miyamoto_2010_CircRes_107_476,
	abstract = {RATIONALE: The recently discovered PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) selectively dephosphorylates Akt at Ser473 and terminates Akt signaling in cancer cells. The regulatory role of PHLPP-1 in the heart has not been considered. OBJECTIVE: To test the hypothesis that blockade/inhibition of PHLPP-1 could constitute a novel way to enhance Akt signals and provide cardioprotection. METHODS AND RESULTS: PHLPP-1 is expressed in neonatal rat ventricular myocytes (NRVMs) and in adult mouse ventricular myocytes (AMVMs). PHLPP-1 knockdown by small interfering RNA significantly enhances phosphorylation of Akt (p-Akt) at Ser473, but not at Thr308, in NRVMs stimulated with leukemia inhibitory factor (LIF). The increased phosphorylation is accompanied by greater Akt catalytic activity. PHLPP-1 knockdown enhances LIF-mediated cardioprotection against doxorubicin and also protects cardiomyocytes against H(2)O(2). Direct Akt effects at mitochondria have been implicated in cardioprotection and mitochondria/cytosol fractionation revealed a significant enrichment of PHLPP-1 at mitochondria. The ability of PHLPP-1 knockdown to potentiate LIF-mediated increases in p-Akt at mitochondria and an accompanying increase in mitochondrial hexokinase-II was demonstrated. We generated PHLPP-1 knockout (KO) mice and demonstrate that AMVMs isolated from KO mice show potentiated p-Akt at Ser473 in response to agonists. When isolated perfused hearts are subjected to ischemia/reperfusion, p-Akt in whole-heart homogenates and in the mitochondrial fraction is significantly increased. Additionally in PHLPP-1 KO hearts, the increase in p-Akt elicited by ischemia/reperfusion is potentiated and, concomitantly, infarct size is significantly reduced. CONCLUSIONS: These results implicate PHLPP-1 as an endogenous negative regulator of Akt activity and cell survival in the heart.},
	article-doi = {10.1161/CIRCRESAHA.109.215020},
	article-pii = {CIRCRESAHA.109.215020},
	author = {Miyamoto, Shigeki and Purcell, Nicole H. and Smith, Jeffrey M. and Gao, Tianyan and Whittaker, Ross and Huang, Katherine and Castillo, Rene and Glembotski, Chris C. and Sussman, Mark A. and Newton, Alexandra C. and Brown, Joan Heller},
	comment = {Circ Res. 2010 Aug 20;107(4):448-50. PMID: 20724723},
	completed = {20100916},
	electronic-issn = {1524-4571},
	electronic-publication = {20100624},
	grantno = {GM067946/GM/NIGMS NIH HHS/United States},
	history = {2010/09/18 06:00 [medline]},
	issue = {4},
	journal = {Circulation research},
	keywords = {Animals, Cell Survival/physiology, Down-Regulation/physiology, Enzyme Activation/physiology, Heart/*physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium/cytology/*metabolism, Nuclear Proteins/deficiency/*physiology, Phosphoprotein Phosphatases/deficiency/*physiology, Proto-Oncogene Proteins c-akt/*metabolism, Rats},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.109.215020 [doi]},
	manuscript-id = {NIHMS242965},
	month = {Aug},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {476--84},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 3.1.3.16 (Phosphoprotein Phosphatases)},
	revised = {20191210},
	source = {Circ Res. 2010 Aug 20;107(4):476-84. doi: 10.1161/CIRCRESAHA.109.215020. Epub 2010 Jun 24.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {PHLPP-1 negatively regulates Akt activity and survival in the heart.},
	title-abbreviation = {Circ Res},
	volume = {107},
	year = {2010}
}

@article{Borillo_2010_CircRes_106_1265,
	abstract = {RATIONALE: Cardioprotective signaling mediates antiapoptotic actions through multiple mechanisms including maintenance of mitochondrial integrity. Pim-1 kinase is an essential downstream effector of AKT-mediated cardioprotection but the mechanistic basis for maintenance of mitochondrial integrity by Pim-1 remains unexplored. This study details antiapoptotic actions responsible for enhanced cell survival in cardiomyocytes with elevated Pim-1 activity. OBJECTIVE: The purpose of this study is to demonstrate that the cardioprotective kinase Pim-1 acts to inhibit cell death by preserving mitochondrial integrity in cardiomyocytes. METHODS AND RESULTS: A combination of biochemical, molecular, and microscopic analyses demonstrate beneficial effects of Pim-1 on mitochondrial integrity. Pim-1 protein level increases in the mitochondrial fraction with a corresponding decrease in the cytosolic fraction of myocardial lysates from hearts subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Cardiac-specific overexpression of Pim-1 results in higher levels of antiapoptotic Bcl-X(L) and Bcl-2 compared to samples from normal hearts. In response to oxidative stress challenge, Pim-1 preserves the inner mitochondrial membrane potential. Ultrastructure of the mitochondria is maintained by Pim-1 activity, which prevents swelling induced by calcium overload. Finally, mitochondria isolated from hearts created with cardiac-specific overexpression of Pim-1 show inhibition of cytochrome c release triggered by a truncated form of proapoptotic Bid. CONCLUSION: Cardioprotective action of Pim-1 kinase includes preservation of mitochondrial integrity during cardiomyopathic challenge conditions, thereby raising the potential for Pim-1 kinase activation as a therapeutic interventional approach to inhibit cell death by antagonizing proapoptotic Bcl-2 family members that regulate the intrinsic apoptotic pathway.},
	article-doi = {10.1161/CIRCRESAHA.109.212035},
	article-pii = {CIRCRESAHA.109.212035},
	author = {Borillo, Gwynngelle A. and Mason, Matt and Quijada, Pearl and V{\"o}lkers, Mirko and Cottage, Christopher and McGregor, Michael and Din, Shabana and Fischer, Kimberlee and Gude, Natalie and Avitabile, Daniele and Barlow, Steven and Alvarez, Roberto and Truffa, Silvia and Whittaker, Ross and Glassy, Matthew S. and Gustafsson, Asa B. and Miyamoto, Shigeki and Glembotski, Christopher C. and Gottlieb, Roberta A. and Brown, Joan Heller and Sussman, Mark A.},
	completed = {20100430},
	electronic-issn = {1524-4571},
	electronic-publication = {20100304},
	grantno = {P01 AG023071/AG/NIA NIH HHS/United States},
	history = {2010/05/01 06:00 [medline]},
	issue = {7},
	journal = {Circulation research},
	keywords = {Animals, Animals, Newborn, *Apoptosis, BH3 Interacting Domain Death Agonist Protein/metabolism, Cell Survival, Cells, Cultured, Cytochromes c/metabolism, Disease Models, Animal, Humans, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Mitochondria, Heart/*enzymology/ultrastructure, Mitochondrial Swelling, Myocardial Reperfusion Injury/enzymology/genetics/pathology/*prevention \& control, Myocytes, Cardiac/*enzymology/ultrastructure, Oxidative Stress, Protein Transport, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-pim-1/genetics/*metabolism, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins/metabolism, Time Factors, Transfection, bcl-X Protein/metabolism},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.109.212035 [doi]},
	manuscript-id = {NIHMS190291},
	month = {Apr},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1265--74},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)},
	revised = {20181113},
	source = {Circ Res. 2010 Apr 16;106(7):1265-74. doi: 10.1161/CIRCRESAHA.109.212035. Epub 2010 Mar 4.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Pim-1 kinase protects mitochondrial integrity in cardiomyocytes.},
	title-abbreviation = {Circ Res},
	volume = {106},
	year = {2010}
}

@article{Belmont_2010_CircRes_106_307,
	abstract = {RATIONALE: Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response, which restores efficient ER protein folding, thus leading to protection from stress. In part, the unfolded protein response alleviates ER stress and cell death by increasing the degradation of terminally misfolded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor (ATF)6, which can induce genes that encode components of the ERAD machinery. OBJECTIVE: Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart. METHODS AND RESULTS: In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from simulated ischemia-induced cell death, whereas dominant-negative Derl3 decreased ERAD and increased simulated ischemia-induced cardiomyocyte death. CONCLUSIONS: This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.},
	article-doi = {10.1161/CIRCRESAHA.109.203901},
	article-pii = {CIRCRESAHA.109.203901},
	author = {Belmont, Peter J. and Chen, Wenqiong J. and {San Pedro}, Matthew N. and Thuerauf, Donna J. and {Gellings Lowe}, Nicole and Gude, Natalie and Hilton, Brett and Wolkowicz, Roland and Sussman, Mark A. and Glembotski, Christopher C.},
	completed = {20100315},
	electronic-issn = {1524-4571},
	electronic-publication = {20091125},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2010/03/17 06:00 [medline]},
	issue = {2},
	journal = {Circulation research},
	keywords = {Activating Transcription Factor 6/genetics/metabolism, Animals, Animals, Newborn, Cell Hypoxia, Cell Survival, Cells, Cultured, Endoplasmic Reticulum/*metabolism, Gene Expression Profiling, Humans, Immunoblotting, Membrane Proteins/genetics/*metabolism, Mice, Mice, Transgenic, MicroRNAs/genetics, Microscopy, Confocal, Myocardial Infarction/genetics/metabolism/pathology, Myocardial Ischemia/genetics/*metabolism/pathology, Myocardium/*metabolism/pathology, Myocytes, Cardiac/cytology/drug effects/metabolism, Promoter Regions, Genetic/genetics, Rats, Reverse Transcriptase Polymerase Chain Reaction, Transduction, Genetic, Tunicamycin/pharmacology},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.109.203901 [doi]},
	manuscript-id = {NIHMS166934},
	month = {Feb},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {307--16},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {11089-65-9 (Tunicamycin)},
	revised = {20181113},
	source = {Circ Res. 2010 Feb 5;106(2):307-16. doi: 10.1161/CIRCRESAHA.109.203901. Epub 2009 Nov 25.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart.},
	title-abbreviation = {Circ Res},
	volume = {106},
	year = {2010}
}

@article{Meex_2009_ArteriosclerThrombVascBiol_29_1322,
	abstract = {OBJECTIVE: Activating transcription factor 6 (ATF6) is a sensor of the endoplasmic reticulum stress response and regulates expression of several key lipogenic genes. We used a 2-stage design to investigate whether ATF6 polymorphisms are associated with lipids in subjects at increased risk for cardiovascular disease (CVD). METHODS AND RESULTS: In stage 1, 13 tag-SNPs were tested for association in Dutch samples ascertained for familial combined hyperlipidemia (FCHL) or increased risk for CVD (CVR). In stage 2, we further investigated the SNP with the strongest association from stage 1, a Methionine/Valine substitution at amino-acid 67, in Finnish FCHL families and in subjects with CVR from METSIM, a Finnish population-based cohort. The combined analysis of both stages reached region-wide significance (P=9 x 10(-4)), but this association was not seen in the entire METSIM cohort. Our functional analysis demonstrated that Valine at position 67 augments ATF6 protein and its targets Grp78 and Grp94 as well as increases luciferase expression through Grp78 promoter. CONCLUSIONS: A common nonsynonymous variant in ATF6 increases ATF6 protein levels and is associated with cholesterol levels in subjects at increased risk for CVD, but this association was not seen in a population-based cohort. Further replication is needed to confirm the role of this variant in lipids.},
	article-doi = {10.1161/ATVBAHA.108.180240},
	article-pii = {ATVBAHA.108.180240},
	author = {Meex, Steven J. R. and Weissglas-Volkov, Daphna and van der Kallen, Carla J. H. and Thuerauf, Donna J. and van Greevenbroek, Marleen M. J. and Schalkwijk, Casper G. and Stehouwer, Coen D. A. and Feskens, Edith J. M. and Heldens, Lonneke and Ayoubi, Torik A. and Hofker, Marten H. and Wouters, Bradly G. and Vlietinck, Robert and Sinsheimer, Janet S. and Taskinen, Marja-Riitta and Kuusisto, Johanna and Laakso, Markku and de Bruin, Tjerk W. A. and Pajukanta, P{\"a}ivi and Glembotski, Christopher C.},
	completed = {20090908},
	electronic-issn = {1524-4636},
	electronic-publication = {20090810},
	grantno = {R01 HL082762-01A1/HL/NHLBI NIH HHS/United States},
	history = {2009/09/09 06:00 [medline]},
	issue = {9},
	journal = {Arteriosclerosis, thrombosis, and vascular biology},
	keywords = {Activating Transcription Factor 6/blood/*genetics, Amino Acid Substitution, Apolipoproteins B/blood, Cardiovascular Diseases/blood/*genetics, Cholesterol/*blood, Cohort Studies, Finland, Genetic Predisposition to Disease, HeLa Cells, Heat-Shock Proteins/genetics/metabolism, Humans, Hyperlipidemia, Familial Combined/blood/*genetics, Membrane Glycoproteins/metabolism, Methionine, Netherlands, *Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Assessment, Transfection, Up-Regulation, Valine},
	language = {eng},
	linking-issn = {1079-5642},
	location-id = {10.1161/ATVBAHA.108.180240 [doi]},
	manuscript-id = {NIHMS116766},
	month = {Sep},
	nlm-unique-id = {9505803},
	owner = {NLM},
	pages = {1322--7},
	print-issn = {1079-5642},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20181201},
	source = {Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1322-7. doi: 10.1161/ATVBAHA.108.180240. Epub 2009 Aug 10.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels.},
	title-abbreviation = {Arterioscler Thromb Vasc Biol},
	volume = {29},
	year = {2009}
}

@article{Doroudgar_2009_JBiolChem_284_29735,
	abstract = {Stresses that perturb the folding of nascent endoplasmic reticulum (ER) proteins activate the ER stress response. Upon ER stress, ER-associated ATF6 is cleaved; the resulting active cytosolic fragment of ATF6 translocates to the nucleus, binds to ER stress response elements (ERSEs), and induces genes, including the ER-targeted chaperone, GRP78. Recent studies showed that nutrient and oxygen starvation during tissue ischemia induce certain ER stress response genes, including GRP78; however, the role of ATF6 in mediating this induction has not been examined. In the current study, simulating ischemia (sI) in a primary cardiac myocyte model system caused a reduction in the level of ER-associated ATF6 with a coordinate increase of ATF6 in nuclear fractions. An ERSE in the GRP78 gene not previously shown to be required for induction by other ER stresses was found to bind ATF6 and to be critical for maximal ischemia-mediated GRP78 promoter induction. Activation of ATF6 and the GRP78 promoter, as well as grp78 mRNA accumulation during sI, were reversed upon simulated reperfusion (sI/R). Moreover, dominant-negative ATF6, or ATF6-targeted miRNA blocked sI-mediated grp78 induction, and the latter increased cardiac myocyte death upon simulated reperfusion, demonstrating critical roles for endogenous ATF6 in ischemia-mediated ER stress activation and cell survival. This is the first study to show that ATF6 is activated by ischemia but inactivated upon reperfusion, suggesting that it may play a role in the induction of ER stress response genes during ischemia that could have a preconditioning effect on cell survival during reperfusion.},
	article-doi = {10.1074/jbc.M109.018036},
	article-pii = {M109.018036},
	author = {Doroudgar, Shirin and Thuerauf, Donna J. and Marcinko, Marie C. and Belmont, Peter J. and Glembotski, Christopher C.},
	completed = {20091123},
	electronic-issn = {1083-351X},
	electronic-publication = {20090721},
	grantno = {HL-085577/HL/NHLBI NIH HHS/United States},
	history = {2009/12/16 06:00 [medline]},
	issue = {43},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Active Transport, Cell Nucleus, Animals, Cell Hypoxia, Cell Nucleus/genetics/*metabolism, Cell Survival/genetics, Endoplasmic Reticulum/genetics/*metabolism, *Gene Expression Regulation, Heat-Shock Proteins/biosynthesis/genetics, Humans, Myocardial Reperfusion Injury/genetics/*metabolism, Myocytes, Cardiac/*metabolism, RNA, Messenger/biosynthesis/genetics, Rats, Stress, Physiological},
	language = {eng},
	linking-issn = {0021-9258},
	location-id = {10.1074/jbc.M109.018036 [doi]},
	month = {Oct},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {29735--45},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20210309},
	source = {J Biol Chem. 2009 Oct 23;284(43):29735-45. doi: 10.1074/jbc.M109.018036. Epub 2009 Jul 21.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response.},
	title-abbreviation = {J Biol Chem},
	volume = {284},
	year = {2009}
}

@article{Whittaker_2009_AmJPhysiolHeartCircPhysiol_296_H1633,
	abstract = {alphaB-crystallin (alphaBC) is a small heat shock protein expressed at high levels in the myocardium where it protects from ischemia-reperfusion damage. Ischemia-reperfusion activates p38 MAP kinase, leading to the phosphorylation of alphaBC on serine 59 (P-alphaBC-S59), enhancing its ability to protect myocardial cells from damage. In the heart, ischemia-reperfusion also causes the translocation of alphaBC from the cytosol to other cellular locations, one of which was recently shown to be mitochondria. However, it is not known whether alphaBC translocates to mitochondria during ischemia-reperfusion, nor is it known whether alphaBC phosphorylation takes place before or after translocation. In the present study, analyses of mitochondrial fractions isolated from mouse hearts subjected to various times of ex vivo ischemia-reperfusion showed that alphaBC translocation to mitochondria was maximal after 20 min of ischemia and then declined steadily during reperfusion. Phosphorylation of mitochondrial alphaBC was maximal after 30 min of ischemia, suggesting that at least in part it occurred after alphaBC association with mitochondria. Consistent with this was the finding that translocation of activated p38 to mitochondria was maximal after only 10 min of ischemia. The overexpression of alphaBC-AAE, which mimics alphaBC phosphorylated on serine 59, has been shown to stabilize mitochondrial membrane potential and to inhibit apoptosis. In the present study, infection of neonatal rat cardiac myocytes with adenovirus-encoded alphaBC-AAE decreased peroxide-induced mitochondrial cytochrome c release. These results suggest that during ischemia alphaBC translocates to mitochondria, where it is phosphorylated and contributes to modulating mitochondrial damage upon reperfusion.},
	article-doi = {10.1152/ajpheart.01227.2008},
	article-pii = {H-01227-2008},
	author = {Whittaker, R. and Glassy, M. S. and Gude, N. and Sussman, M. A. and Gottlieb, R. A. and Glembotski, C. C.},
	completed = {20090619},
	electronic-issn = {1522-1539},
	electronic-publication = {20090227},
	grantno = {HL-085577/HL/NHLBI NIH HHS/United States},
	history = {2009/06/20 09:00 [medline]},
	issue = {5},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Animals, Animals, Newborn, Cells, Cultured, Cytochromes c/metabolism, Hydrogen Peroxide/toxicity, Kinetics, Mice, Mice, Inbred C57BL, Mitochondria, Heart/drug effects/enzymology/*metabolism, Myocardial Infarction/enzymology/*metabolism/pathology, *Myocardial Reperfusion, Myocardial Reperfusion Injury/enzymology/*metabolism/pathology, Phosphorylation, Protein Transport, Rats, Transduction, Genetic, alpha-Crystallin B Chain/genetics/*metabolism, p38 Mitogen-Activated Protein Kinases/metabolism},
	language = {eng},
	linking-issn = {0363-6135},
	location-id = {10.1152/ajpheart.01227.2008 [doi]},
	month = {May},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H1633--42},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)},
	revised = {20200930},
	source = {Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1633-42. doi: 10.1152/ajpheart.01227.2008. Epub 2009 Feb 27.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Kinetics of the translocation and phosphorylation of alphaB-crystallin in mouse heart mitochondria during ex vivo ischemia.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {296},
	year = {2009}
}

@article{Yuan_2009_AmJPhysiolHeartCircPhysiol_296_H470,
	abstract = {Bacterial endotoxin lipopolysaccharide (LPS) is responsible for the multiorgan dysfunction that characterizes septic shock and is causal in the myocardial depression that is a common feature of endotoxemia in patients. In this setting the myocardial dysfunction appears to be due, in part, to the production of proinflammatory cytokines. A line of evidence also indicates that LPS stimulates autophagy in cardiomyocytes. However, the signal transduction pathway leading to autophagy and its role in the heart are incompletely characterized. In this work, we wished to determine the effect of LPS on autophagy and the physiological significance of the autophagic response. Autophagy was monitored morphologically and biochemically in HL-1 cardiomyocytes, neonatal rat cardiomyocytes, and transgenic mouse hearts after the administration of bacterial LPS or TNF-alpha. We observed that autophagy was increased after exposure to LPS or TNF-alpha, which is induced by LPS. The inhibition of TNF-alpha production by AG126 significantly reduced the accumulation of autophagosomes both in cell culture and in vivo. The inhibition of p38 MAPK or nitric oxide synthase by pharmacological inhibitors also reduced autophagy. Nitric oxide or H(2)O(2) induced autophagy in cardiomyocytes, whereas N-acetyl-cysteine, a potent antioxidant, suppressed autophagy. LPS resulted in increased reactive oxygen species (ROS) production and decreased total glutathione. To test the hypothesis that autophagy might serve as a damage control mechanism to limit further ROS production, we induced autophagy with rapamycin before LPS exposure. The activation of autophagy by rapamycin suppressed LPS-mediated ROS production and protected cells against LPS toxicity. These findings support the notion that autophagy is a cytoprotective response to LPS-induced cardiomyocyte injury; additional studies are needed to determine the therapeutic implications.},
	article-doi = {10.1152/ajpheart.01051.2008},
	article-pii = {H-01051-2008},
	author = {Yuan, Hua and Perry, Cynthia N. and Huang, Chengqun and Iwai-Kanai, Eri and Carreira, Raquel S. and Glembotski, Christopher C. and Gottlieb, Roberta A.},
	completed = {20090312},
	electronic-issn = {1522-1539},
	electronic-publication = {20081219},
	grantno = {R01 AG033283/AG/NIA NIH HHS/United States},
	history = {2009/03/13 09:00 [medline]},
	issue = {2},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Acetylcysteine/pharmacology, Animals, Animals, Newborn, Antioxidants/pharmacology, Autophagy/*drug effects, Cells, Cultured, *Cytoprotection, Enzyme Inhibitors/pharmacology, Glutathione/metabolism, Hydrogen Peroxide/metabolism, Imidazoles/pharmacology, Lipopolysaccharides/*pharmacology, Mice, Mice, Transgenic, Mitochondria, Heart/drug effects/metabolism/pathology, Myocytes, Cardiac/*drug effects/metabolism/pathology, Nitric Oxide/metabolism, Nitric Oxide Donors/pharmacology, Nitric Oxide Synthase/antagonists \& inhibitors/metabolism, Nitroprusside/pharmacology, Oxidative Stress/*drug effects, Pyridines/pharmacology, Rats, Signal Transduction/*drug effects, Sirolimus/pharmacology, Tumor Necrosis Factor-alpha/metabolism, Tyrphostins/pharmacology, omega-N-Methylarginine/pharmacology, p38 Mitogen-Activated Protein Kinases/antagonists \& inhibitors/metabolism},
	language = {eng},
	linking-issn = {0363-6135},
	location-id = {10.1152/ajpheart.01051.2008 [doi]},
	month = {Feb},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H470--9},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {WYQ7N0BPYC (Acetylcysteine)},
	revised = {20200930},
	source = {Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H470-9. doi: 10.1152/ajpheart.01051.2008. Epub 2008 Dec 19.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {296},
	year = {2009}
}

@article{Tadimalla_2008_CircRes_103_1249,
	abstract = {The endoplasmic reticulum (ER) stress response (ERSR) is activated when folding of nascent proteins in the ER lumen is impeded. Myocardial ischemia was recently shown to activate the ERSR; however, the role of this complex signaling system in the heart is not well understood. ER stress activates the transcription factor ATF6, which induces expression of proteins targeted to the ER, where they restore protein folding, thus fostering cytoprotection. We previously developed a transgenic mouse line that expresses a conditionally activated form of ATF6 in the heart. In this mouse line, ATF6 activation decreased ischemic damage in an ex vivo model of myocardial ischemia/reperfusion and induced numerous genes, including mesencephalic astrocyte-derived neurotrophic factor (MANF). In the present study, MANF expression was shown to be induced in cardiac myocytes and in other cell types in the hearts of mice subjected to in vivo myocardial infarction. Additionally, simulated ischemia induced MANF in an ATF6-dependent manner in neonatal rat ventricular myocyte cultures. In contrast to many other ER-resident ERSR proteins, MANF lacks a canonical ER-retention sequence, consistent with our finding that MANF was readily secreted from cultured cardiac myocytes. Knockdown of endogenous MANF with micro-RNA increased cell death upon simulated ischemia/reperfusion, whereas addition of recombinant MANF to media protected cultured cardiac myocytes from simulated ischemia/reperfusion-mediated death. Thus, a possible function of the ERSR in the heart is the ischemia-mediated induction of secreted proteins, such as MANF, that can function in an autocrine/paracrine manner to modulate myocardial damage from ER stresses, including ischemia.},
	article-doi = {10.1161/CIRCRESAHA.108.180679},
	article-pii = {CIRCRESAHA.108.180679},
	author = {Tadimalla, Archana and Belmont, Peter J. and Thuerauf, Donna J. and Glassy, Matthew S. and Martindale, Joshua J. and Gude, Natalie and Sussman, Mark A. and Glembotski, Christopher C.},
	completed = {20081231},
	electronic-issn = {1524-4571},
	electronic-publication = {20081016},
	grantno = {P01 HL085577/HL/NHLBI NIH HHS/United States},
	history = {2008/10/18 09:00 [entrez]},
	issue = {11},
	journal = {Circulation research},
	keywords = {Activating Transcription Factor 6/genetics/*physiology, Animals, Animals, Newborn, Astrocytes/*physiology, Cells, Cultured, Endoplasmic Reticulum/*physiology, Heart/*physiology, Heart Ventricles, Mesencephalon/*physiology, Mice, Mice, Transgenic, Muscle Cells/*physiology, Myocardial Infarction/genetics/physiopathology/surgery, Nerve Growth Factors, Nerve Tissue Proteins/genetics/physiology, Polymerase Chain Reaction, Rats, Stress, Physiological},
	language = {eng},
	linking-issn = {0009-7330},
	location-id = {10.1161/CIRCRESAHA.108.180679 [doi]},
	manuscript-id = {NIHMS126745},
	month = {Nov},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1249--58},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {0 (Nerve Tissue Proteins)},
	revised = {20181113},
	source = {Circ Res. 2008 Nov 21;103(11):1249-58. doi: 10.1161/CIRCRESAHA.108.180679. Epub 2008 Oct 16.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Mesencephalic astrocyte-derived neurotrophic factor is an ischemia-inducible secreted endoplasmic reticulum stress response protein in the heart.},
	title-abbreviation = {Circ Res},
	volume = {103},
	year = {2008}
}

@article{Belmont_2008_JBiolChem_283_14012,
	abstract = {Exposing cells to conditions that modulate growth can impair endoplasmic reticulum (ER) protein folding, leading to ER stress and activation of the transcription factor, ATF6. ATF6 binds to ER stress response elements in target genes, inducing expression of proteins that enhance the ER protein folding capacity, which helps overcome the stress and foster survival. To examine the mechanism of ATF6-mediated survival in vivo, we developed a transgenic mouse model that expresses a novel conditionally activated form of ATF6. We previously showed that activating ATF6 protected the hearts of ATF6 transgenic mice from ER stresses. In the present study, transcript profiling identified modulatory calcineurin interacting protein-1 (MCIP1), also known as regulator of calcineurin 1 (RCAN1), as a novel ATF6-inducible gene that encodes a known regulator of calcineurin/nuclear factor of activated T cells (NFAT)-mediated growth and development in many tissues. The ability of ATF6 to induce RCAN1 in vivo was replicated in cultured cardiac myocytes, where adenoviral (AdV)-mediated overexpression of activated ATF6 induced the RCAN1 promoter, up-regulated RCAN1 mRNA, inhibited calcineurin phosphatase activity, and exerted a striking growth modulating effect that was inhibited by RCAN1-targeted small interfering RNA. These results demonstrate that RCAN1 is a novel ATF6 target gene that may coordinate growth and ER stress signaling pathways. By modulating growth, RCAN1 may reduce the need for ER protein folding, thus helping to overcome the stress and enhance survival. Moreover, these results suggest that RCAN1 may also be a novel integrator of growth and ER stress signaling in many other tissues that depend on calcineurin/NFAT signaling for optimal growth and development.},
	article-doi = {10.1074/jbc.M709776200},
	article-pii = {14012},
	author = {Belmont, Peter J. and Tadimalla, Archana and Chen, Wenqiong J. and Martindale, Joshua J. and Thuerauf, Donna J. and Marcinko, Marie and Gude, Natalie and Sussman, Mark A. and Glembotski, Christopher C.},
	completed = {20080709},
	electronic-issn = {1083-351X},
	electronic-publication = {20080303},
	grantno = {HL-085577/HL/NHLBI NIH HHS/United States},
	history = {2008/03/06 09:00 [entrez]},
	issue = {20},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6/*metabolism, Animals, Calcium-Binding Proteins, Cells, Cultured, Endoplasmic Reticulum/*metabolism, Intracellular Signaling Peptides and Proteins/*metabolism, Mice, Mice, Transgenic, Models, Biological, Models, Statistical, Muscle Proteins/*metabolism, Myocardium/metabolism, Oligonucleotide Array Sequence Analysis, RNA/metabolism, RNA, Small Interfering/metabolism, Rats, Signal Transduction},
	language = {eng},
	linking-issn = {0021-9258},
	location-id = {10.1074/jbc.M709776200 [doi]},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {14012--21},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {63231-63-0 (RNA)},
	revised = {20210206},
	source = {J Biol Chem. 2008 May 16;283(20):14012-21. doi: 10.1074/jbc.M709776200. Epub 2008 Mar 3.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene.},
	title-abbreviation = {J Biol Chem},
	volume = {283},
	year = {2008}
}

@article{Glembotski_2008_JMolCellCardiol_44_453,
	abstract = {The misfolding of nascent proteins, or the unfolding of proteins after synthesis is complete, can occur in response to numerous environmental stresses, or as a result of mutations that de-stabilize protein structure. Cells have developed elaborate protein quality control systems that recognize improperly folded proteins and either refold them or facilitate their degradation. One such quality control system is the unfolded protein response, or the UPR. The UPR is a highly conserved signal transduction system that is activated when cells are subjected to conditions that alter the endoplasmic reticulum (ER) in ways that impair the folding of nascent proteins in this organelle. Recent observations indicate that in the heart, the UPR is activated during acute stresses, including ischemia/reperfusion, as well as upon longer term stresses that lead to cardiac hypertrophy and heart failure. Moreover, certain aspects of the UPR are activated during, and are required for proper heart development. This review summarizes recent studies of the UPR in the heart, focusing on the possible roles of the UPR in contributing to, or protecting from ischemia/reperfusion damage.},
	article-doi = {10.1016/j.yjmcc.2007.10.017},
	article-pii = {S0022-2828(07)01283-7},
	author = {Glembotski, Christopher C.},
	completed = {20080804},
	electronic-issn = {1095-8584},
	electronic-publication = {20071203},
	grantno = {R01 NS025037-20/NS/NINDS NIH HHS/United States},
	history = {2007/12/07 09:00 [entrez]},
	issue = {3},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Endoplasmic Reticulum/metabolism, Humans, Myocardium/*metabolism, Protein Folding, Proteins/chemistry/*metabolism, Reperfusion Injury/metabolism/physiopathology, Signal Transduction/*physiology},
	language = {eng},
	linking-issn = {0022-2828},
	manuscript-id = {NIHMS44225},
	month = {Mar},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {453--9},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {0 (Proteins)},
	revised = {20181113},
	source = {J Mol Cell Cardiol. 2008 Mar;44(3):453-9. doi: 10.1016/j.yjmcc.2007.10.017. Epub 2007 Dec 3.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The role of the unfolded protein response in the heart.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {44},
	year = {2008}
}

@article{Muraski_2007_NatMed_13_1467,
	abstract = {The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.},
	address = {United States},
	article-doi = {10.1038/nm1671},
	article-pii = {nm1671},
	author = {Muraski, John A. and Rota, Marcello and Misao, Yu and Fransioli, Jenna and Cottage, Christopher and Gude, Natalie and Esposito, Grazia and Delucchi, Francesca and Arcarese, Michael and Alvarez, Roberto and Siddiqi, Sailay and Emmanuel, Gregory N. and Wu, Weitao and Fischer, Kimberlee and Martindale, Joshua J. and Glembotski, Christopher C. and Leri, Annarosa and Kajstura, Jan and Magnuson, Nancy and Berns, Anton and Beretta, Remus M. and Houser, Steven R. and Schaefer, Erik M. and Anversa, Piero and Sussman, Mark A.},
	comment = {Nat Med. 2008 Mar;14(3):350},
	completed = {20080221},
	electronic-issn = {1546-170X},
	electronic-publication = {20071125},
	grantno = {5R01HL067245/HL/NHLBI NIH HHS/United States},
	history = {2007/11/27 09:00 [entrez]},
	issue = {12},
	journal = {Nature medicine},
	keywords = {Animals, Apoptosis, Cell Nucleus/metabolism, Humans, Mice, Mice, Knockout, Myocardium/metabolism, Myocytes, Cardiac/*metabolism, Proto-Oncogene Proteins c-akt/*metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-pim-1/biosynthesis/*physiology, Rats, bcl-X Protein/metabolism},
	language = {eng},
	linking-issn = {1078-8956},
	month = {Dec},
	nlm-unique-id = {9502015},
	owner = {NLM},
	pages = {1467--75},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)},
	revised = {20120625},
	source = {Nat Med. 2007 Dec;13(12):1467-75. doi: 10.1038/nm1671. Epub 2007 Nov 25.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Pim-1 regulates cardiomyocyte survival downstream of Akt.},
	title-abbreviation = {Nat Med},
	volume = {13},
	year = {2007}
}

@article{Jin_2008_AmJPhysiolHeartCircPhysiol_294_H337,
	abstract = {The cytosolic small heat shock protein alphaB-crystallin (alphaBC) is a molecular chaperone expressed in large quantities in the heart, where it protects from stresses such as ischemia-reperfusion (I/R). Upon I/R, p38 MAP kinase activation leads to phosphorylation of alphaBC on Ser(59) (P-alphaBC-S59), which increases its protective ability. alphaBC confers protection, in part, by interacting with and affecting the functions of key components in stressed cells. We investigated the hypothesis that protection from I/R damage in the heart by P-alphaBC-S59 can be mediated by localization to mitochondria. We found that P-alphaBC-S59 localized to mitochondria isolated from untreated mouse hearts and that this localization increased more than threefold when the hearts were subjected to ex vivo I/R. Mitochondrial P-alphaBC-S59 decreased when hearts were treated with the p38 inhibitor SB-202190. Moreover, SB-202190-treated hearts exhibited more tissue damage and less functional recovery upon reperfusion than controls. I/R activates mitochondrial permeability transition (MPT) pore opening, which increases cell damage. We found that mitochondria incubated with a recombinant mutant form of alphaBC that mimics P-alphaBC-S59 exhibited decreased calcium-induced MPT pore opening. These results indicate that mitochondria may be among the key components in stressed cells with which P-alphaBC-S59 interacts and that this localization may protect the myocardium, in part, by modulating MPT pore opening and, thus, reducing I/R injury.},
	address = {United States},
	article-doi = {10.1152/ajpheart.00881.2007},
	article-pii = {00881.2007},
	author = {Jin, J.-K. and Whittaker, R. and Glassy, M. S. and Barlow, S. B. and Gottlieb, R. A. and Glembotski, C. C.},
	completed = {20080228},
	electronic-publication = {20071109},
	grantno = {HL 75573/HL/NHLBI NIH HHS/United States},
	history = {2007/11/13 09:00 [entrez]},
	issue = {1},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Animals, Calcium/metabolism, Cytosol/metabolism, Female, Imidazoles/pharmacology, In Vitro Techniques, Mice, Mice, Inbred C3H, Mitochondria, Heart/drug effects/enzymology/*metabolism, Mitochondrial Membrane Transport Proteins/metabolism, Mitochondrial Permeability Transition Pore, Mutation, Myocardial Reperfusion Injury/enzymology/metabolism/*prevention \& control, Myocardium/enzymology/*metabolism, Phosphorylation, Protein Kinase Inhibitors/pharmacology, Pyridines/pharmacology, Recombinant Proteins/metabolism, Subcellular Fractions/metabolism, Time Factors, alpha-Crystallin B Chain/genetics/*metabolism, p38 Mitogen-Activated Protein Kinases/antagonists \& inhibitors/metabolism},
	language = {eng},
	linking-issn = {0363-6135},
	month = {Jan},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H337--44},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20201209},
	source = {Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H337-44. doi: 10.1152/ajpheart.00881.2007. Epub 2007 Nov 9.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Localization of phosphorylated alphaB-crystallin to heart mitochondria during ischemia-reperfusion.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {294},
	year = {2008}
}

@article{Glembotski_2007_CircRes_101_975,
	abstract = {Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, approximately 30\% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease.},
	address = {United States},
	article-doi = {10.1161/CIRCRESAHA.107.161273},
	article-pii = {101/10/975},
	author = {Glembotski, Christopher C.},
	completed = {20071213},
	electronic-issn = {1524-4571},
	grantno = {HL-085577/HL/NHLBI NIH HHS/United States},
	history = {2007/11/10 09:00 [entrez]},
	issue = {10},
	journal = {Circulation research},
	keywords = {Animals, Cardiovascular Diseases/*metabolism/pathology, Endoplasmic Reticulum/chemistry/*metabolism, Humans, Myocardium/*metabolism/pathology, Protein Folding, Protein Transport/*physiology},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Nov},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {975--84},
	publication-status = {ppublish},
	revised = {20071109},
	source = {Circ Res. 2007 Nov 9;101(10):975-84. doi: 10.1161/CIRCRESAHA.107.161273.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Endoplasmic reticulum stress in the heart.},
	title-abbreviation = {Circ Res},
	volume = {101},
	year = {2007}
}

@article{Glembotski_2007_JCellBiol_179_371,
	abstract = {A study by Rybkin et al. (see p. 527) substantially advances our understanding of regulated exocytois by specialized secretory cells, such as atrial myocytes. A second member of the Ras-related protein family, RRP17, was identified and shown to participate in regulating the secretion of the cardiac-derived peptide hormone, atrial natriuretic peptide. In addition to the heart, RRP17 was shown to be expressed in neuronal, pancreatic, and skeletal muscle cells, suggesting a widespread role in regulated secretion for this new protein.},
	article-doi = {10.1083/jcb.200710021},
	article-pii = {200710021},
	author = {Glembotski, Christopher C.},
	comment = {J Cell Biol. 2007 Nov 5;179(3):527-37. PMID: 17984325},
	completed = {20071212},
	electronic-issn = {1540-8140},
	electronic-publication = {20071029},
	grantno = {NS025037/NS/NINDS NIH HHS/United States},
	history = {2007/10/31 09:00 [entrez]},
	issue = {3},
	journal = {The Journal of cell biology},
	keywords = {Animals, Atrial Natriuretic Factor/*biosynthesis/physiology, Exocytosis, Heart Atria/*metabolism/*pathology, Hormones/metabolism, Humans, Models, Biological, Muscle Cells/metabolism, Muscle, Skeletal/metabolism, Neurons/metabolism, Pancreas/metabolism, Peptides/chemistry, ras Proteins/*biosynthesis/*physiology},
	language = {eng},
	linking-issn = {0021-9525},
	month = {Nov},
	nlm-unique-id = {0375356},
	owner = {NLM},
	pages = {371--3},
	print-issn = {0021-9525},
	publication-status = {ppublish},
	registry-number = {EC 3.6.5.2 (ras Proteins)},
	revised = {20181113},
	source = {J Cell Biol. 2007 Nov 5;179(3):371-3. doi: 10.1083/jcb.200710021. Epub 2007 Oct 29.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Getting a G--RRP on regulated exocytosis in the heart.},
	title-abbreviation = {J Cell Biol},
	volume = {179},
	year = {2007}
}

@article{Thuerauf_2007_JBiolChem_282_22865,
	abstract = {The endoplasmic reticulum (ER)-transmembrane proteins, ATF6 alpha and ATF6 beta, are cleaved during the ER stress response (ERSR). The resulting N-terminal fragments (N-ATF6 alpha and N-ATF6 beta) have conserved DNA-binding domains and divergent transcriptional activation domains. N-ATF6 alpha and N-ATF6 beta translocate to the nucleus, bind to specific regulatory elements, and influence expression of ERSR genes, such as glucose-regulated protein 78 (GRP78), that contribute to resolving the ERSR, thus, enhancing cell viability. We previously showed that N-ATF6 alpha is a rapidly degraded, strong transcriptional activator, whereas beta is a slowly degraded, weak activator. In this study we explored the molecular basis and functional impact of these isoform-specific characteristics in HeLa cells. Mutants in the transcriptional activation domain or DNA-binding domain of N-ATF6 alpha exhibited loss of function and increased expression, the latter of which suggested decreased rates of degradation. Fusing N-ATF6 alpha to the mutant estrogen receptor generated N-ATF6 alpha-MER, which, without tamoxifen exhibited loss-of-function and high expression, but in the presence of tamoxifen N-ATF6 alpha-MER exhibited gain-of-function and low expression. N-ATF6 beta conferred loss-of-function and high expression to N-ATF6 alpha, suggesting that ATF6 beta is an endogenous inhibitor of ATF6 alpha. In vitro DNA binding experiments showed that recombinant N-ATF6 beta inhibited the binding of recombinant N-ATF6 alpha to an ERSR element from the GRP78 promoter. Moreover, siRNA-mediated knock-down of endogenous ATF6 beta increased GRP78 promoter activity and GRP78 gene expression, as well as augmenting cell viability. Thus, the relative levels of ATF6 alpha and -beta, may contribute to regulating the strength and duration of ATF6-dependent ERSR gene induction and cell viability.},
	address = {United States},
	article-doi = {10.1074/jbc.M701213200},
	article-pii = {S0021-9258(20)54744-3},
	author = {Thuerauf, Donna J. and Marcinko, Marie and Belmont, Peter J. and Glembotski, Christopher C.},
	completed = {20070913},
	electronic-publication = {20070523},
	grantno = {NS025037/NS/NINDS NIH HHS/United States},
	history = {2007/05/25 09:00 [entrez]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6/*chemistry, Basic-Leucine Zipper Transcription Factors/*chemistry, Cell Survival, Cytomegalovirus/metabolism, DNA/chemistry, Endoplasmic Reticulum/*metabolism, *Gene Expression Regulation, HeLa Cells, Heat-Shock Proteins/metabolism, Humans, Molecular Chaperones/metabolism, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, RNA, Small Interfering/metabolism, Transcriptional Activation, beta-Galactosidase/metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {22865--78},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20210209},
	source = {J Biol Chem. 2007 Aug 3;282(31):22865-78. doi: 10.1074/jbc.M701213200. Epub 2007 May 23.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability.},
	title-abbreviation = {J Biol Chem},
	volume = {282},
	year = {2007}
}

@article{Thuerauf_2006_CircRes_99_275,
	abstract = {Endoplasmic reticulum (ER) stresses that reduce ER protein folding activate the unfolded protein response (UPR). One effector of the UPR is the transcription factor X-box binding protein-1 (XBP1), which is expressed on ER stress-mediated splicing of the XBP1 mRNA. XBP1 induces certain ER-targeted proteins, eg, glucose-regulated protein 78 (GRP78), that help resolve the ER stress and foster cell survival. In this study, we determined whether hypoxia can activate the UPR in the cardiac context. Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.},
	address = {United States},
	article-doi = {10.1161/01.RES.0000233317.70421.03},
	article-pii = {01.RES.0000233317.70421.03},
	author = {Thuerauf, Donna J. and Marcinko, Marie and Gude, Natalie and Rubio, Marta and Sussman, Mark A. and Glembotski, Christopher C.},
	completed = {20061005},
	electronic-issn = {1524-4571},
	electronic-publication = {20060622},
	grantno = {NS/HL-25037/HL/NHLBI NIH HHS/United States},
	history = {2006/06/24 09:00 [entrez]},
	issue = {3},
	journal = {Circulation research},
	keywords = {Animals, Animals, Newborn, Basic-Leucine Zipper Transcription Factors/genetics/physiology, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, Heat-Shock Proteins/genetics, Hypoxia/*metabolism, Mice, Molecular Chaperones/genetics, Myocardial Infarction/*pathology, Myocytes, Cardiac/*pathology, Neoplasm Proteins/genetics/physiology, Protein Folding, RNA Splicing, Rats, Regulatory Factor X Transcription Factors, Transcription Factors, X-Box Binding Protein 1},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Aug},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {275--82},
	publication-status = {ppublish},
	registry-number = {0 (Xbp1 protein, rat)},
	revised = {20210309},
	source = {Circ Res. 2006 Aug 4;99(3):275-82. doi: 10.1161/01.RES.0000233317.70421.03. Epub 2006 Jun 22.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes.},
	title-abbreviation = {Circ Res},
	volume = {99},
	year = {2006}
}

@article{Wall_2006_AmJPhysiolHeartCircPhysiol_291_H2462,
	abstract = {Ischemia-reperfusion (I/R) has critical consequences in the heart. Recent studies on the functions of I/R-activated kinases, such as p38 mitogen-activated protein kinase (MAPK), showed that I/R injury is reduced in the hearts of transgenic mice that overexpress the p38 MAPK activator MAPK kinase 6 (MKK6). This protection may be fostered by changes in the levels of many proteins not currently known to be regulated by p38. To examine this possibility, we employed the multidimensional protein identification technology MudPIT to characterize changes in levels of proteins in MKK6 transgenic mouse hearts, focusing on proteins in mitochondria, which play key roles in mediating I/R injury in the heart. Of the 386 mitochondrial proteins identified, the levels of 58 were decreased, while only 2 were increased in the MKK6 transgenic mouse hearts. Among those that were decreased were 21 mitochondrial oxidative phosphorylation complex proteins, which was unexpected because p38 is not known to mediate such decreases. Immunoblotting verified that proteins in each of the five oxidative phosphorylation complexes were reduced in MKK6 mouse hearts. On assessing functional consequences of these reductions, we found that MKK6 mouse heart mitochondria exhibited 50\% lower oxidative respiration and I/R-mediated reactive oxygen species (ROS) generation, both of which are predicted consequences of decreased oxidative phosphorylation complex proteins. Thus the cardioprotection observed in MKK6 transgenic mouse hearts may be partly due to decreased electron transport, which is potentially beneficial, because damaging ROS are known to be generated by mitochondrial complexes I and III during reoxygenation.},
	address = {United States},
	article-doi = {10.1152/ajpheart.01311.2005},
	article-pii = {01311.2005},
	author = {Wall, Jason A. and Wei, Jing and Ly, Mimi and Belmont, Peter and Martindale, Joshua J. and Tran, Diem and Sun, Jun and Chen, Wenqiong J. and Yu, Wen and Oeller, Paul and Briggs, Steve and Gustafsson, Asa B. and Sayen, M. R. and Gottlieb, Roberta A. and Glembotski, Christopher C.},
	completed = {20070112},
	electronic-publication = {20060609},
	grantno = {NS/HL-25037/HL/NHLBI NIH HHS/United States},
	history = {2006/06/13 09:00 [entrez]},
	issue = {5},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Animals, Heart/*physiology, MAP Kinase Kinase 6/genetics/*metabolism, Mice, Mice, Transgenic, Mitochondria, Heart/genetics/metabolism, Models, Biological, *Oxidative Phosphorylation, Proteins/genetics/*metabolism, p38 Mitogen-Activated Protein Kinases/*metabolism},
	language = {eng},
	linking-issn = {0363-6135},
	month = {Nov},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H2462--72},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {EC 2.7.12.2 (MAP Kinase Kinase 6)},
	revised = {20200930},
	source = {Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2462-72. doi: 10.1152/ajpheart.01311.2005. Epub 2006 Jun 9.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {291},
	year = {2006}
}

@article{Martindale_2006_CircRes_98_1186,
	abstract = {Ischemia/reperfusion (I/R) affects the integrity of the endoplasmic reticulum (ER), the site of synthesis and folding of numerous proteins. Therefore, I/R may activate the unfolded protein response (UPR), resulting in the induction of a collection of ER stress proteins, many of which are protective and function to resolve the ER stress. In this study, we showed that when mouse hearts were subjected to ex vivo I/R, the levels of 2 ER stress-inducible markers of the UPR, the ER-targeted cytoprotective chaperones glucose-regulated proteins 78 and 94 (GRP78 and GRP94), were increased, consistent with I/R-mediated UPR activation in the heart. The UPR-mediated activation of ATF6 (Activation of Transcription Factor 6) induces cytoprotective ER stress proteins, including GRP78 and GRP94. To examine whether ATF6 protects the myocardium from I/R injury in the heart, we generated transgenic (TG) mice featuring cardiac-restricted expression of a novel tamoxifen-activated form of ATF6, ATF6-MER. When NTG and ATF6-MER TG mice were treated with or without tamoxifen for 5 days, only the hearts from the tamoxifen-treated TG mice exhibited increased levels of many ER stress-inducible mRNAs and proteins; for example, GRP78 and GRP94 transcript levels were increased by 8- and 15-fold, respectively. The tamoxifen-treated TG mouse hearts also exhibited better functional recovery from ex vivo I/R, as well as significantly reduced necrosis and apoptosis. These results suggest that the UPR is activated in the heart during I/R and that, as a result, the ATF6 branch of the UPR may induce expression of proteins that can function to reduce I/R injury.},
	address = {United States},
	article-doi = {10.1161/01.RES.0000220643.65941.8d},
	article-pii = {01.RES.0000220643.65941.8d},
	author = {Martindale, Joshua J. and Fernandez, Rayne and Thuerauf, Donna and Whittaker, Ross and Gude, Natalie and Sussman, Mark A. and Glembotski, Christopher C.},
	comment = {Circ Res. 2006 May 12;98(9):1120-2. PMID: 16690892},
	completed = {20060616},
	electronic-issn = {1524-4571},
	electronic-publication = {20060406},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {2006/04/08 09:00 [entrez]},
	issue = {9},
	journal = {Circulation research},
	keywords = {Activating Transcription Factor 6/genetics/*metabolism, Animals, Cardiotonic Agents/*metabolism, Cells, Cultured, Echocardiography, Endoplasmic Reticulum/*metabolism, Female, Gene Expression Regulation, Heat-Shock Proteins/genetics/*metabolism, Male, Membrane Glycoproteins/genetics/*metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic/genetics, Molecular Chaperones/genetics/*metabolism, Myocardial Reperfusion Injury/*diagnostic imaging/physiopathology, Myocardium/metabolism, Protein Folding, RNA, Messenger/metabolism, Recovery of Function, Stress, Physiological/genetics/*metabolism, Tamoxifen/*pharmacology, Transcriptional Activation},
	language = {eng},
	linking-issn = {0009-7330},
	month = {May},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1186--93},
	publication-status = {ppublish},
	registry-number = {YCYIS6GADR (molecular chaperone GRP78)},
	revised = {20181201},
	source = {Circ Res. 2006 May 12;98(9):1186-93. doi: 10.1161/01.RES.0000220643.65941.8d. Epub 2006 Apr 6.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6.},
	title-abbreviation = {Circ Res},
	volume = {98},
	year = {2006}
}

@article{Kato_2005_JClinInvest_115_2716,
	abstract = {This study delineates a mechanism for antiapoptotic signaling initiated by atrial natriuretic peptide (ANP) stimulation leading to elevation of cGMP levels and subsequent nuclear accumulation of Akt kinase associated with zyxin, a cytoskeletal LIM-domain protein. Nuclear targeting of zyxin induces resistance to cell death coincident with nuclear accumulation of activated Akt. Nuclear translocation of zyxin triggered by cGMP also promotes nuclear Akt accumulation. Additional supportive evidence for nuclear accumulation of zyxin-enhancing cardiomyocyte survival includes the following: (a) promotion of zyxin nuclear localization by cardioprotective stimuli; (b) zyxin association with phospho-Akt473 induced by cardioprotective stimuli; and (c) recruitment of zyxin to the nucleus by activated nuclear-targeted Akt as well as recruitment of Akt by nuclear-targeted zyxin. Nuclear accumulation of zyxin requires both Akt activation and nuclear localization. Potentiation of cell survival is sensitive to stimulation intensity with high-level induction by ANP or cGMP signaling leading to apoptotic cell death rather than enhancing resistance to apoptotic stimuli. Myocardial nuclear accumulation of zyxin and Akt responds similarly in vivo following treatment of mice with ANP or cGMP. Thus, zyxin and activated Akt participate in a cGMP-dependent signaling cascade leading from ANP receptors to nuclear accumulation of both molecules. Nuclear accumulation of zyxin and activated Akt may represent a fundamental mechanism that facilitates nuclear-signal transduction and potentiates cell survival.},
	article-doi = {10.1172/JCI24280},
	article-pii = {24280},
	author = {Kato, Takahiro and Muraski, John and Chen, Yan and Tsujita, Yasuyuki and Wall, Jason and Glembotski, Christopher C. and Schaefer, Erik and Beckerle, Mary and Sussman, Mark A.},
	completed = {20051212},
	grantno = {HL58224/HL/NHLBI NIH HHS/United States},
	history = {2005/10/04 09:00 [entrez]},
	issue = {10},
	journal = {The Journal of clinical investigation},
	keywords = {Active Transport, Cell Nucleus/drug effects/genetics, Animals, Animals, Newborn, Apoptosis/drug effects, Atrial Natriuretic Factor/metabolism/*pharmacology, Cell Nucleus/*metabolism, Cell Survival/drug effects/genetics, Cells, Cultured, Cyclic GMP/*metabolism, Cytoskeletal Proteins/genetics/*metabolism, Humans, Mice, Mice, Knockout, Myocytes, Cardiac/cytology/*metabolism, Proto-Oncogene Proteins c-akt/*metabolism, Rats, Rats, Sprague-Dawley, Signal Transduction/drug effects/genetics, Zyxin},
	language = {eng},
	linking-issn = {0021-9738},
	month = {Oct},
	nlm-unique-id = {7802877},
	owner = {NLM},
	pages = {2716--30},
	print-issn = {0021-9738},
	publication-status = {ppublish},
	registry-number = {H2D2X058MU (Cyclic GMP)},
	revised = {20181113},
	source = {J Clin Invest. 2005 Oct;115(10):2716-30. doi: 10.1172/JCI24280.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt.},
	title-abbreviation = {J Clin Invest},
	volume = {115},
	year = {2005}
}

@article{McMullen_2005_JBiolChem_280_20995,
	abstract = {Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.},
	address = {United States},
	article-doi = {10.1074/jbc.M407060200},
	article-pii = {S0021-9258(20)61536-8},
	author = {McMullen, Meghan E. and Bryant, Patrick W. and Glembotski, Christopher C. and Vincent, Peter A. and Pumiglia, Kevin M.},
	completed = {20050712},
	electronic-publication = {20050324},
	grantno = {T32-HL-07194/HL/NHLBI NIH HHS/United States},
	history = {2005/03/26 09:00 [entrez]},
	issue = {22},
	journal = {The Journal of biological chemistry},
	keywords = {Actins/chemistry/metabolism, Apoptosis, Binding Sites, Blotting, Western, Cell Cycle Proteins, Cell Movement, Cell Proliferation, Cells, Cultured, Culture Media, Serum-Free/pharmacology, Cytoskeleton/metabolism, Dual Specificity Phosphatase 1, Endothelium, Vascular/cytology/*metabolism, Enzyme Inhibitors/pharmacology, Fibroblast Growth Factors/metabolism, Green Fluorescent Proteins/metabolism, HSP27 Heat-Shock Proteins, Heat-Shock Proteins/metabolism, Humans, Immediate-Early Proteins, MAP Kinase Kinase 1/metabolism, MAP Kinase Kinase 2/metabolism, MAP Kinase Kinase 6/metabolism, MAP Kinase Signaling System, Models, Biological, Molecular Chaperones, Mutation, Neoplasm Proteins/metabolism, Neovascularization, Pathologic, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 1, Protein Tyrosine Phosphatases, Time Factors, Umbilical Veins/cytology, Vascular Endothelial Growth Factor A/metabolism, p38 Mitogen-Activated Protein Kinases/*metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {20995--1003},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.1.3.48 (Protein Tyrosine Phosphatases)},
	revised = {20210209},
	source = {J Biol Chem. 2005 Jun 3;280(22):20995-1003. doi: 10.1074/jbc.M407060200. Epub 2005 Mar 24.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Activation of p38 has opposing effects on the proliferation and migration of endothelial cells.},
	title-abbreviation = {J Biol Chem},
	volume = {280},
	year = {2005}
}

@article{Martindale_2005_JBiolChem_280_669,
	abstract = {The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, alpha B-crystallin (alpha BC), in cultured cardiac myocytes, we examined alpha BC levels in the mouse hearts. The level of alpha BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in alpha BC levels in the mitochondrial fractions of TG mouse hearts but no increase in alpha BC levels in any of the other fractions analyzed. These alterations in alpha BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.},
	article-doi = {10.1074/jbc.M406690200},
	article-pii = {S0021-9258(20)76634-2},
	author = {Martindale, Joshua J. and Wall, Jason A. and Martinez-Longoria, Diana M. and Aryal, Prafulla and Rockman, Howard A. and Guo, Yiru and Bolli, Roberto and Glembotski, Christopher C.},
	completed = {20050721},
	electronic-issn = {1083-351X},
	electronic-publication = {20041018},
	grantno = {R01 HL068088/HL/NHLBI NIH HHS/United States},
	history = {2004/10/20 09:00 [entrez]},
	issue = {1},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Enzyme Activation, Gene Expression Regulation, Enzymologic, Humans, In Vitro Techniques, MAP Kinase Kinase 3/genetics/metabolism, MAP Kinase Kinase 6/*biosynthesis/genetics, Mice, Mice, Transgenic, Myocardial Infarction/*enzymology/physiopathology/prevention \& control, Myocardial Reperfusion Injury/*enzymology/physiopathology, Organ Specificity, Recovery of Function, alpha-Crystallin B Chain/metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	manuscript-id = {NIHMS480435},
	month = {Jan},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {669--76},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.7.12.2 (MAP2K6 protein, human)},
	revised = {20210206},
	source = {J Biol Chem. 2005 Jan 7;280(1):669-76. doi: 10.1074/jbc.M406690200. Epub 2004 Oct 18.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo.},
	title-abbreviation = {J Biol Chem},
	volume = {280},
	year = {2005}
}

@article{Thuerauf_2004_JBiolChem_279_21078,
	abstract = {The endoplasmic reticulum (ER) transmembrane proteins, ATF6alpha and ATF6beta, are cleaved in response to ER stress, which can be induced by tunicamycin. The resulting N-terminal fragments of both ATF6 isoforms, which have conserved basic leucine-zipper and DNA binding domains but divergent transcriptional activation domains, translocate to the nucleus where they bind to ER stress-response elements (ERSE) in ER stress-response genes (ERSRG), such as GRP78. Although it is known that ATF6alpha is a potent activator of ERSRGs, the transcriptional potency and functions of ATF6beta remain to be explored. Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6alpha and N-ATF6beta) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6alpha conferred approximately 200-fold greater GRP78 promoter activation than N-ATF6beta. Because ER stress activates nuclear translocation of both ATF6alpha and beta and because both bind to ERSEs, the effect of co-expressing them on GRP78 induction was assessed. Surprisingly, N-ATF6beta inhibited N-ATF6alpha-mediated GRP78 promoter activation in a dominant-negative manner. Moreover, N-ATF6beta inhibited TN-mediated GRP78 promoter activation, which requires endogenous ATF6alpha. ATF6 isoform-specific small inhibitory RNAs were used to show that, as expected, endogenous ATF6alpha was required for maximal ERSRG induction; however, endogenous ATF6beta moderated ERSRG induction. These results indicate that compared with ATF6alpha, ATF6beta is a very poor activator of ERSRG induction and it represses ATF6alpha-mediated ERSRG induction. Thus, ATF6beta may serve as a transcriptional repressor functioning in part to regulate the strength and duration of ATF6alpha-mediated ERSRG activation during the ER stress response.},
	address = {United States},
	article-doi = {10.1074/jbc.M400713200},
	article-pii = {S0021-9258(20)66966-6},
	author = {Thuerauf, Donna J. and Morrison, Lisa and Glembotski, Christopher C.},
	completed = {20040721},
	electronic-publication = {20040218},
	grantno = {NS 025037/NS/NINDS NIH HHS/United States},
	history = {2004/02/20 05:00 [entrez]},
	issue = {20},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6, Basic-Leucine Zipper Transcription Factors, Cytomegalovirus/enzymology/genetics, DNA-Binding Proteins/genetics/*metabolism, Endoplasmic Reticulum/*physiology, Gene Expression Regulation/*genetics, Genes, Reporter, HeLa Cells, Humans, Kinetics, Leucine Zippers, Protein Isoforms/metabolism, RNA, Small Interfering/genetics, Transcription Factors/genetics/*metabolism, Transcriptional Activation, beta-Galactosidase/genetics/metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {21078--84},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.2.1.23 (beta-Galactosidase)},
	revised = {20210209},
	source = {J Biol Chem. 2004 May 14;279(20):21078-84. doi: 10.1074/jbc.M400713200. Epub 2004 Feb 18.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction.},
	title-abbreviation = {J Biol Chem},
	volume = {279},
	year = {2004}
}

@article{Morrison_2004_AmJPhysiolHeartCircPhysiol_286_H847,
	abstract = {Overexpression studies have shown that the small heat shock proteins (sHSP) protect the myocardium from ischemia-reperfusion (I/R)-induced damage. However, gene deletion studies are necessary to demonstrate whether sHSPs are required for protection. The genes for alphaB-crystallin (alphaBC) and HSPB2, two sHSPs that are expressed in high levels in the heart, are in close proximity to one another; as a result, both genes were disrupted in a recently generated knockout (KO) mouse line. The alphaBC/HSPB2 KO mouse line is currently the only model that features disruption of sHSPs normally expressed in the heart. Accordingly, we examined the cardiac morphology, function, and response to I/R-induced stress in alphaBC-HSPB2 KO mice. Initial gross, light microscopic and echocardiographic characterization showed that the morphological and functional properties of hearts from adult KO mice were indistinguishable from age-matched wild-type (WT) mice. Electron microscopy showed that, compared with WT mouse hearts, KO mouse heart sarcomeres were relatively normal. Isolated perfused KO mouse hearts displayed normal contractility; however, when compared with WT, after I/R, KO mouse hearts exhibited a twofold reduction in contractile recovery, as well as increased necrosis and apoptosis. Additionally, when compared with WT, KO mouse hearts exhibited 43\% less reduced glutathione, which is known to protect from I/R-induced damage. Thus, whereas neither alphaBC nor HSPB2 is essential for myocardial development and function under nonstressful conditions, one or both are required for maximal functional recovery and protection from I/R-induced necrosis and apoptosis.},
	address = {United States},
	article-doi = {10.1152/ajpheart.00715.2003},
	article-pii = {00715.2003},
	author = {Morrison, Lisa E. and Whittaker, Ross J. and Klepper, Robert E. and Wawrousek, Eric F. and Glembotski, Christopher C.},
	completed = {20040401},
	electronic-publication = {20031030},
	grantno = {NS/HL-25037/NS/NINDS NIH HHS/United States},
	history = {2003/11/01 05:00 [entrez]},
	issue = {3},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Animals, Apoptosis, Disease Models, Animal, HSP27 Heat-Shock Proteins, Heat-Shock Proteins/genetics/*physiology, Mice, Mice, Inbred Strains, Mice, Knockout, Myocardial Contraction, Myocardial Reperfusion Injury/pathology/*physiopathology, Myocardium/metabolism/pathology, Necrosis, Phenotype, alpha-Crystallin B Chain/genetics/*physiology},
	language = {eng},
	linking-issn = {0363-6135},
	month = {Mar},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H847--55},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {0 (alpha-Crystallin B Chain)},
	revised = {20200930},
	source = {Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H847-55. doi: 10.1152/ajpheart.00715.2003. Epub 2003 Oct 30.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Roles for alphaB-crystallin and HSPB2 in protecting the myocardium from ischemia-reperfusion-induced damage in a KO mouse model.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {286},
	year = {2004}
}

@article{Andrews_2003_CardiovascRes_59_46,
	abstract = {OBJECTIVE: Our goal was to determine if the MKK6-p38 MAPK pathway regulates cardiac intracellular calcium ([Ca(2+)](i)). We also tested if MKK6 might influence expression of SERCA2, a calcium regulatory molecule involved in relaxation, and the activity of nuclear factor of activated T-cells (NF-AT), a calcium-regulated transcription factor that participates in pathological responses to pressure-overload. METHODS: Neonatal rat ventricular myocytes were transfected with MKK6(Glu), an activator of p38 MAPK. Green fluorescent protein (GFP) was used as transfection marker and [Ca(2+)](i) was evaluated via indo-1. SERCA2 expression was assayed via Northern and Western techniques. The activity of the rat SERCA2 gene promoter and NF-AT-dependent gene expression were monitored with reporter genes. Myocyte contractility was regulated by electrical pacing. RESULTS: MKK6(Glu) prolonged decay of the contractile calcium transients, downregulated SERCA2 expression, and reduced the activity of the rat SERCA2 gene promoter. Diastolic [Ca(2+)](i) in myocytes pacing at 1-2 Hz was dramatically increased by MKK6(Glu). NF-AT-dependent gene expression was activated by MKK6(Glu) and by pacing of contractions in a synergistic manner. Overexpression of SERCA2 mitigated the effects of MKK6(Glu) on [Ca(2+)](i) and NF-AT. CONCLUSIONS: The MKK6(Glu)-p38 MAPK pathway prolongs the decay phase of the cardiac contractile calcium by downregulating SERCA2, increasing diastolic [Ca(2+)](i) which activates NF-AT. The ability of SERCA2 over-expression to reduce NF-AT activity represents a potential novel therapeutic effect of SERCA2 that should be further considered in the development of cardiac gene therapy strategies.},
	address = {England},
	article-doi = {10.1016/s0008-6363(03)00329-8},
	article-pii = {S0008636303003298},
	author = {Andrews, Catherine and Ho, Peter D. and Dillmann, Wolfgang H. and Glembotski, Christopher C. and McDonough, Patrick M.},
	completed = {20031014},
	grantno = {HL-63975/HL/NHLBI NIH HHS/United States},
	history = {2003/06/28 05:00 [entrez]},
	issue = {1},
	journal = {Cardiovascular research},
	keywords = {Animals, Animals, Newborn, Calcium/metabolism, Calcium-Calmodulin-Dependent Protein Kinases/genetics/*metabolism, Calcium-Transporting ATPases/genetics/*metabolism, Cells, Cultured, DNA-Binding Proteins/genetics/*metabolism, Electric Stimulation, Gene Expression, Green Fluorescent Proteins, Image Processing, Computer-Assisted, Luminescent Proteins/genetics, MAP Kinase Kinase 6, *MAP Kinase Signaling System, Microscopy, Fluorescence, Mitogen-Activated Protein Kinases/genetics/*metabolism, Myocytes, Cardiac/*metabolism, NFATC Transcription Factors, *Nuclear Proteins, RNA, Messenger/analysis, Rats, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Transcription Factors/genetics/*metabolism, Transfection, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0008-6363},
	month = {Jul},
	nlm-unique-id = {0077427},
	owner = {NLM},
	pages = {46--56},
	print-issn = {0008-6363},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20191210},
	source = {Cardiovasc Res. 2003 Jul 1;59(1):46-56. doi: 10.1016/s0008-6363(03)00329-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The MKK6-p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT.},
	title-abbreviation = {Cardiovasc Res},
	volume = {59},
	year = {2003}
}

@article{Degousee_2003_CircRes_92_757,
	abstract = {Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38alpha and p38beta2 MAPK mRNA in rat cardiac myocytes. Interleukin-1beta induced the phosphorylation of p38alpha and p38beta2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38beta2 MAPK inhibited interleukin-1beta-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38alpha and p38beta2 MAPK inhibitor, SB202190, attenuated interleukin-1beta-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38beta2 MAPK, in the absence of interleukin-1beta, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1beta-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.},
	address = {United States},
	article-doi = {10.1161/01.RES.0000067929.01404.03},
	article-pii = {01.RES.0000067929.01404.03},
	author = {Degousee, Norbert and Martindale, Joshua and Stefanski, Eva and Cieslak, Martin and Lindsay, Thomas F. and Fish, Jason E. and Marsden, Philip A. and Thuerauf, Donna J. and Glembotski, Christopher C. and Rubin, Barry B.},
	completed = {20030425},
	electronic-issn = {1524-4571},
	electronic-publication = {20030320},
	grantno = {NS/HL-25037/NS/NINDS NIH HHS/United States},
	history = {2003/03/22 04:00 [entrez]},
	issue = {7},
	journal = {Circulation research},
	keywords = {Animals, Animals, Genetically Modified, Animals, Newborn, Calcium-Calmodulin-Dependent Protein Kinases/genetics/*metabolism, Cells, Cultured, Cyclooxygenase 2, Dinoprostone/metabolism, Enzyme Inhibitors/pharmacology, Gene Expression Regulation, Enzymologic/drug effects, Heart Ventricles/cytology/metabolism, Imidazoles/pharmacology, Interleukin-1/pharmacology, Isoenzymes/genetics/*metabolism, MAP Kinase Kinase 6, MAP Kinase Signaling System/drug effects/*physiology, Mitogen-Activated Protein Kinases/antagonists \& inhibitors/genetics/*metabolism, Myocytes, Cardiac/cytology/drug effects/*metabolism, Phosphorylation/drug effects, Prostaglandin-Endoperoxide Synthases/genetics/*metabolism, Pyridines/pharmacology, RNA, Messenger/drug effects/genetics/metabolism, Rats, Rats, Sprague-Dawley, Tubulin/metabolism, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Apr},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {757--64},
	publication-status = {ppublish},
	registry-number = {PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)},
	revised = {20181130},
	source = {Circ Res. 2003 Apr 18;92(7):757-64. doi: 10.1161/01.RES.0000067929.01404.03. Epub 2003 Mar 20.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo.},
	title-abbreviation = {Circ Res},
	volume = {92},
	year = {2003}
}

@article{OBrien_2003_CircRes_92_589,
	abstract = {Generation of proapoptotic sphingolipids by neutral sphingomyelinase activation is an early response to hypoxia/reoxygenation (HR) in cardiomyocytes. Factor associated with neutral sphingomyelinase activation (FAN) mediates activation of sphingomyelinase and subsequent apoptosis. However, the participation of FAN in HR-induced cardiomyocyte cell death has not been elucidated. We therefore investigated the expression and role of FAN in rat cardiomyocytes. A cDNA was isolated from rat heart encoding putative rat FAN. Reverse transcriptase-polymerase chain reaction, immunoelectron microscopy, and immunofluorescence demonstrated for the first time the expression of FAN specifically in rat cardiomyocytes. FAN expression was confirmed by the finding that expression of a dominant-negative FAN almost completely abrogated HR-induced cell death, whereas overexpression of wild-type FAN led to an increase. Treatment of FAN and dominant-negative FAN--expressing cells with C2-ceramide produced substantial cell death, indicating dominant-negative FAN exerts its protective action by interfering with the activation of the sphingolipid cascade. Taking these results together, we conclude that FAN is a previously undescribed and important HR signaling component in the heart and that inhibition of FAN may provide a novel intervention point for reducing ischemia/reperfusion injury.},
	address = {United States},
	article-doi = {10.1161/01.RES.0000066290.29715.67},
	article-pii = {01.RES.0000066290.29715.67},
	author = {O'Brien, Nicole W. and Gellings, Nicole M. and Guo, Mei and Barlow, Steven B. and Glembotski, Christopher C. and Sabbadini, Roger A.},
	completed = {20030429},
	electronic-issn = {1524-4571},
	electronic-publication = {20030313},
	grantno = {NS-HLBI-25037/NS/NINDS NIH HHS/United States},
	history = {2003/03/15 04:00 [entrez]},
	issue = {6},
	journal = {Circulation research},
	keywords = {Adaptor Proteins, Vesicular Transport/chemistry/*physiology, Amino Acid Sequence, Animals, *Apoptosis, Cell Hypoxia, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Myocytes, Cardiac/cytology/*metabolism, Proteins/chemistry/*physiology, Rats, Sequence Alignment},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Apr},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {589--91},
	publication-status = {ppublish},
	registry-number = {0 (Proteins)},
	revised = {20071114},
	source = {Circ Res. 2003 Apr 4;92(6):589-91. doi: 10.1161/01.RES.0000066290.29715.67. Epub 2003 Mar 13.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Factor associated with neutral sphingomyelinase activation and its role in cardiac cell death.},
	title-abbreviation = {Circ Res},
	volume = {92},
	year = {2003}
}

@article{Morrison_2003_CircRes_92_203,
	abstract = {AlphaB-crystallin (alphaBC), a small heat shock protein expressed in high levels in the heart, is phosphorylated on Ser-19, 45, and 59 after stress. However, it is not known whether alphaBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode forms of alphaBC harboring Ser to Ala (blocks phosphorylation) or Ser to Glu (mimics phosphorylation) mutations at positions 19, 45, and 59. The effects of each form on apoptosis of cultured cardiac myocytes after hyperosmotic or hypoxic stress were assessed. Compared with controls, cells that expressed alphaBC with Ser to Ala substitutions at all three positions, alphaBC(AAA), exhibited more stress-induced apoptosis. Cells expressing either alphaBC(AAE) or (EEE) exhibited 3-fold less apoptosis than cells expressing alphaBC(AAA), indicating that phosphorylation of Ser-59 confers protection. alphaBC is known to bind to procaspase-3 and to decrease caspase-3 activation. Compared with cells expressing alphaBC(AAA), the activation of caspase-3 was decreased by 3-fold in cells expressing alphaBC(AAE). These results demonstrate that mimicking the phosphorylation of alphaBC on Ser-59 is necessary and sufficient to confer caspase-3 inhibition and protection of cardiac myocytes against hyperosmotic or hypoxic stress. These findings provide direct evidence that alphaBC(S59P) contributes to the cardioprotection observed after physiologically relevant stresses, such as transient hypoxia. Identifying the targets of alphaBC(S59P) will reveal important details about the mechanism underlying the cytoprotective effects of this small heat shock protein.},
	address = {United States},
	article-doi = {10.1161/01.res.0000052989.83995.a5},
	author = {Morrison, Lisa E. and Hoover, Holly E. and Thuerauf, Donna J. and Glembotski, Christopher C.},
	comment = {Circ Res. 2003 Feb 7;92(2):130-2. PMID: 12574138},
	completed = {20030214},
	electronic-issn = {1524-4571},
	grantno = {NS/HL-25037/NS/NINDS NIH HHS/United States},
	history = {2003/02/08 04:00 [entrez]},
	issue = {2},
	journal = {Circulation research},
	keywords = {Amino Acid Substitution, Animals, Apoptosis/drug effects/*physiology, Base Sequence, Caspase 3, Caspases/metabolism, Cell Hypoxia/physiology, Cell Survival, Cells, Cultured, In Situ Nick-End Labeling, Molecular Mimicry/genetics, Molecular Sequence Data, Mutagenesis, Site-Directed, Myocytes, Cardiac/cytology/drug effects/*metabolism, Osmolar Concentration, Phosphorylation, Rats, Rats, Sprague-Dawley, Sorbitol/pharmacology, Structure-Activity Relationship, Transfection, alpha-Crystallin B Chain/biosynthesis/*genetics},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Feb},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {203--11},
	publication-status = {ppublish},
	registry-number = {EC 3.4.22.- (Caspases)},
	revised = {20190706},
	source = {Circ Res. 2003 Feb 7;92(2):203-11. doi: 10.1161/01.res.0000052989.83995.a5.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Mimicking phosphorylation of alphaB-crystallin on serine-59 is necessary and sufficient to provide maximal protection of cardiac myocytes from apoptosis.},
	title-abbreviation = {Circ Res},
	volume = {92},
	year = {2003}
}

@article{Cavalli_2003_AmJPhysiolCellPhysiol_284_C780,
	abstract = {Calcium channels are important in a variety of cellular events including muscle contraction, signaling, proliferation, and apoptosis. Sphingolipids have been recognized as mediators of intracellular calcium release through their actions on a calcium channel, sphingolipid calcium release-mediating protein of the endoplasmic reticulum (SCaMPER). The current study investigates the expression and function of SCaMPER in cardiomyocytes. Northern analyses and RT-PCR cloning and sequencing revealed SCaMPER expression in both human and rat cardiac tissue. Immunofluorescence and Western blot analyses demonstrated that SCaMPER is abundant in cardiac tissue and is localized to the sarcotubular junction. This was confirmed by the colocalization of SCaMPER with dihydropyridine and ryanodine receptors by confocal microscopy. Purified T tubules were shown to contain SCaMPER and immunoelectron micrographs suggested that SCaMPER is located to the junctional T tubules, but a junctional SR localization cannot be ruled out. The sphingolipid ligand for SCaMPER, sphingosylphosphorylcholine (SPC), initiated calcium release from the cardiomyocyte SR. Importantly, antisense knockdown of SCaMPER mRNA produced a substantial reduction of sphingolipid-induced calcium release, suggesting that SCaMPER is a potentially important calcium channel of cardiomyocytes.},
	address = {United States},
	article-doi = {10.1152/ajpcell.00382.2002},
	article-pii = {00382.2002},
	author = {Cavalli, Amy L. and O'Brien, Nicole W. and Barlow, Steven B. and Betto, Romeo and Glembotski, Christopher C. and Palade, Philip T. and Sabbadini, Roger A.},
	completed = {20030321},
	electronic-publication = {20021106},
	history = {2002/11/08 04:00 [entrez]},
	issue = {3},
	journal = {American journal of physiology. Cell physiology},
	keywords = {Animals, Animals, Newborn, Calcium/metabolism, Calcium Channels/genetics/*metabolism, Calcium Signaling/*genetics, Cell Membrane/genetics/*metabolism, DNA, Complementary/analysis/genetics, Dimerization, Immunohistochemistry, Intracellular Membranes/metabolism/ultrastructure, Microscopy, Electron, Microtubules/genetics/metabolism/ultrastructure, Molecular Sequence Data, Myocytes, Cardiac/*metabolism/ultrastructure, Protein Structure, Quaternary/genetics, RNA, Messenger/genetics/isolation \& purification, Rats, Ryanodine Receptor Calcium Release Channel/metabolism, Sarcoplasmic Reticulum/genetics/metabolism/ultrastructure, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Sphingolipids/*metabolism},
	language = {eng},
	linking-issn = {0363-6143},
	month = {Mar},
	nlm-unique-id = {100901225},
	owner = {NLM},
	pages = {C780--90},
	print-issn = {0363-6143},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20200930},
	source = {Am J Physiol Cell Physiol. 2003 Mar;284(3):C780-90. doi: 10.1152/ajpcell.00382.2002. Epub 2002 Nov 6.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Expression and functional characterization of SCaMPER: a sphingolipid-modulated calcium channel of cardiomyocytes.},
	title-abbreviation = {Am J Physiol Cell Physiol},
	volume = {284},
	year = {2003}
}

@article{Thuerauf_2002_JBiolChem_277_20734,
	abstract = {ATF6 is a 670-amino acid endoplasmic reticulum (ER) transmembrane protein that is cleaved in response to ER stress. The resulting N-terminal fragment of approximately 400 amino acids translocates to the nucleus and activates selected ER stress-inducible genes, such as GRP-78 and sarco/endoplasmic reticulum ATPase, which are required for cell survival. In studying the mechanism of ATF6-activated transcription, we found that when HeLa cells were transfected with a plasmid encoding ATF6-(1-373), ER stress-inducible reporter gene activation was high, but ATF6-(1-373) expression was low, unless a proteasome inhibitor was added. In contrast, transfection with a plasmid encoding ATF6-(94-373) resulted in low reporter activation and high expression of ATF6-(94-373), which was independent of the proteasome inhibitor. Thus, the information responsible for transcriptional activation and proteasomal degradation must lie within the N-terminal 93 amino acids of ATF6. This portion of ATF6 was found to be homologous to the herpes simplex viral protein, VP16. One 8-amino acid domain of particular interest in this region of ATF6 is 75\% identical to the VN8 region in VP16. VN8 is required for VP16-mediated transcription, as well as rapid degradation of VP16 by proteasomes. Point mutations in the VN8-like region of ATF6 caused a loss of transcription, increased expression levels, and an increase in half-life. Thus, the potent transcriptional activities and rapid degradation of ATF6 and VP16 require the VN8 domains in each protein. Homology searches indicate that ATF6 is the only eukaryotic protein known that possesses an active VN8 domain, raising questions about how this domain evolved and the functional importance underlying its appearance in only these two transcription factors.},
	address = {United States},
	article-doi = {10.1074/jbc.M201749200},
	article-pii = {S0021-9258(20)84924-2},
	author = {Thuerauf, Donna J. and Morrison, Lisa E. and Hoover, Holly and Glembotski, Christopher C.},
	completed = {20020712},
	electronic-publication = {20020321},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {2002/03/23 10:00 [entrez]},
	issue = {23},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6, Amino Acid Sequence, DNA-Binding Proteins/chemistry/metabolism/*physiology, Electrophoresis, Gel, Pulsed-Field, HeLa Cells, Herpes Simplex Virus Protein Vmw65/chemistry/*physiology, Humans, Hydrolysis, Molecular Sequence Data, Sequence Homology, Amino Acid, Transcription Factors/chemistry/metabolism/*physiology, Transcription, Genetic/*physiology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {20734--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {0 (Transcription Factors)},
	revised = {20210206},
	source = {J Biol Chem. 2002 Jun 7;277(23):20734-9. doi: 10.1074/jbc.M201749200. Epub 2002 Mar 21.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Coordination of ATF6-mediated transcription and ATF6 degradation by a domain that is shared with the viral transcription factor, VP16.},
	title-abbreviation = {J Biol Chem},
	volume = {277},
	year = {2002}
}

@article{Post_2002_JBiolChem_277_15286,
	abstract = {Expression of constitutively active Ras (V12Ras) in cultured neonatal rat ventricular myocytes or targeted cardiac expression of V12Ras in transgenic mice induces myocardial cell growth and expression of genes that are markers of cardiac hypertrophy including atrial natriuretic factor (ANF) and myosin light chain-2. However, the signaling pathways that modulate the effects of Ras on acquisition of the various features of cardiac hypertrophy are not known. We identified the Ral guanine nucleotide exchange factor-like factor (Rlf) in a yeast two-hybrid screen of human heart cDNA library using Ras as bait, suggesting that Ras signaling in the heart may involve Rlf. We demonstrate here that Rlf is expressed in human heart. Expression of wild type Rlf or Rlf-CAAX, a membrane-targeted mutant of Rlf, transactivated ANF and myosin light chain-2 promoters but did not activate canonical cAMP responsive elements or phorbol ester responsive elements, suggesting that Rlf expression does not lead to a generalized increase in transcription. Transfection of mutant ANF promoter-reporter gene constructs demonstrated that the proximal serum response element is both necessary and sufficient for Rlf-inducible ANF expression. Rlf-induced ANF promoter activation required Ral and Cdc42 but not RhoA, Rac1, ERK, or p38 kinase activation. In addition, Rlf potentiated alpha(1)-adrenergic receptor (alpha(1)-AR)-induced ANF expression. Prolonged activation of the alpha(1)-AR increases RalGTP levels in neonatal rat ventricular myocytes, further emphasizing a role for Ral guanine nucleotide exchange factors in alpha(1)-AR signaling. Overall, this study supports the concept that Rlf and Ral are important previously unrecognized signaling components that regulate transcriptional responses in myocardial cells.},
	address = {United States},
	article-doi = {10.1074/jbc.M111844200},
	article-pii = {S0021-9258(19)35663-7},
	author = {Post, Ginell R. and Swiderski, Carol and Waldrop, Bruce A. and Salty, Lina and Glembotski, Christopher C. and Wolthuis, Rob M. F. and Mochizuki, Naoki},
	completed = {20020702},
	electronic-publication = {20020214},
	history = {2002/02/16 10:00 [entrez]},
	issue = {18},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Animals, Newborn, Atrial Natriuretic Factor/genetics, Blotting, Northern, Cells, Cultured, *Escherichia coli Proteins, *Gene Expression Regulation, Genes, Reporter, Guanine Nucleotide Exchange Factors/*metabolism, Heart Ventricles, Humans, Mice, Mice, Transgenic, Myocardium/*metabolism, Promoter Regions, Genetic, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-1/*genetics, Repressor Proteins/genetics, Transcriptional Activation, Transfection},
	language = {eng},
	linking-issn = {0021-9258},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {15286--92},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20210209},
	source = {J Biol Chem. 2002 May 3;277(18):15286-92. doi: 10.1074/jbc.M111844200. Epub 2002 Feb 14.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Guanine nucleotide exchange factor-like factor (Rlf) induces gene expression and potentiates alpha 1-adrenergic receptor-induced transcriptional responses in neonatal rat ventricular myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {277},
	year = {2002}
}

@article{Thuerauf_2001_JBiolChem_276_48309,
	abstract = {The recently described transcription factor, ATF6, mediates the expression of proteins that compensate for potentially stressful changes in the endoplasmic reticulum (ER), such as reduced ER calcium. In cardiac myocytes the maintenance of optimal calcium levels in the sarcoplasmic reticulum (SR), a specialized form of the ER, is required for proper contractility. The present study investigated the hypothesis that ATF6 serves as a regulator of the expression of sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2), a protein that transports calcium into the SR from the cytoplasm. Depletion of SR calcium in cultured cardiac myocytes fostered the translocation of ATF6 from the ER to the nucleus, activated the promoter for rat SERCA2, and led to increased levels of SERCA2 protein. SERCA2 promoter induction by calcium depletion was partially blocked by dominant-negative ATF6, whereas constitutively activated ATF6 led to SERCA2 promoter activation. Mutation analyses identified a promoter-proximal ER stress-response element in the rat SERCA2 gene that was required for maximal induction by ATF6 and calcium depletion. Although this element was shown to be responsible for all of the effects of ATF6 on SERCA2 promoter activation, it was responsible for only a portion of the effects of calcium depletion. Thus, SERCA2 induction in response to calcium depletion appears to be a potentially physiologically important compensatory response to this stress that involves intracellular signaling pathways that are both dependent and independent of ATF6.},
	address = {United States},
	article-doi = {10.1074/jbc.M107146200},
	article-pii = {S0021-9258(19)40350-5},
	author = {Thuerauf, D. J. and Hoover, H. and Meller, J. and Hernandez, J. and Su, L. and Andrews, C. and Dillmann, W. H. and McDonough, P. M. and Glembotski, C. C.},
	completed = {20020131},
	electronic-publication = {20011010},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {2001/10/12 10:00 [entrez]},
	issue = {51},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6, Animals, Base Sequence, *Calcium Signaling, Calcium-Transporting ATPases/genetics/*metabolism, Cells, Cultured, DNA Primers, DNA-Binding Proteins/*physiology, Endoplasmic Reticulum/*physiology, Fluorescent Antibody Technique, Gene Expression Regulation, Enzymologic/*physiology, Myocardium/cytology/enzymology/*metabolism, Promoter Regions, Genetic, Rats, Rats, Sprague-Dawley, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Transcription Factors/*physiology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Dec},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {48309--17},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 7.2.2.10 (Calcium-Transporting ATPases)},
	revised = {20210209},
	source = {J Biol Chem. 2001 Dec 21;276(51):48309-17. doi: 10.1074/jbc.M107146200. Epub 2001 Oct 10.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Sarco/endoplasmic reticulum calcium ATPase-2 expression is regulated by ATF6 during the endoplasmic reticulum stress response: intracellular signaling of calcium stress in a cardiac myocyte model system.},
	title-abbreviation = {J Biol Chem},
	volume = {276},
	year = {2001}
}

@article{Degousee_2001_JBiolChem_276_43842,
	abstract = {Group IIa phospholipase A(2) (GIIa PLA(2)) is released by some cells in response to interleukin-1beta. The purpose of this study was to determine whether interleukin-1beta would stimulate the synthesis and release of GIIa PLA(2) from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA(2) in the regulation of this process. Whereas GIIa PLA(2) mRNA was not identified in untreated cells, exposure to interleukin-1beta resulted in the sustained expression of GIIa PLA(2) mRNA. Interleukin-1beta also stimulated a progressive increase in cellular and extracellular GIIa PLA(2) protein levels and increased extracellular PLA(2) activity 70-fold. In addition, interleukin-1beta stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1beta stimulated MAPKAP-K2 activity, GIIa PLA(2) mRNA expression, GIIa PLA(2) protein synthesis, and the release of extracellular PLA(2) activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA(2) protein synthesis and the release of GIIa PLA(2) and increased extracellular PLA(2) activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA(2) protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA(2) protein synthesis and release by interleukin-1beta-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1beta-induced synthesis and release of GIIa PLA(2) by cardiomyocytes.},
	address = {United States},
	article-doi = {10.1074/jbc.M101516200},
	article-pii = {S0021-9258(19)82816-8},
	author = {Degousee, N. and Stefanski, E. and Lindsay, T. F. and Ford, D. A. and Shahani, R. and Andrews, C. A. and Thuerauf, D. J. and Glembotski, C. C. and Nevalainen, T. J. and Tischfield, J. and Rubin, B. B.},
	completed = {20011220},
	electronic-publication = {20010924},
	grantno = {HL42665/HL/NHLBI NIH HHS/United States},
	history = {2001/09/26 10:00 [entrez]},
	issue = {47},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Animals, Newborn, Enzyme Activation, Gene Expression Regulation, Enzymologic/*physiology, Heart/drug effects, Interleukin-1/*pharmacology, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinases/*physiology, Myocardium/cytology/*enzymology, Phospholipases A/biosynthesis/*genetics/metabolism, Phospholipases A2, Protein-Serine-Threonine Kinases/metabolism, RNA, Messenger/genetics/metabolism, Rats, Rats, Sprague-Dawley, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Nov},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {43842--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.1.1.4 (Phospholipases A2)},
	revised = {20210209},
	source = {J Biol Chem. 2001 Nov 23;276(47):43842-9. doi: 10.1074/jbc.M101516200. Epub 2001 Sep 24.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {p38 MAPK regulates group IIa phospholipase A2 expression in interleukin-1beta -stimulated rat neonatal cardiomyocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {276},
	year = {2001}
}

@article{Craig_2001_JBiolChem_276_37621,
	abstract = {Many cell types mount elaborate, compensatory responses to stress that enhance survival; however, the intracellular signals that govern these responses are poorly understood. Cardiotrophin-1 (CT-1), a stress-induced cytokine, belongs to the interleukin-6/glycoprotein 130 receptor-coupled cytokine family. CT-1 is released from the heart in response to hypoxic stress, and it protects cardiac myocytes from hypoxia-induced apoptosis, thus establishing a central role for this cytokine in the cardiac stress response. In the present study, CT-1 activated p38 and ERK MAPKs as well as Akt in cultured cardiac myocytes; these three pathways were activated in a parallel manner. CT-1 also induced the degradation of the NF-kappa B cytosolic anchor, I kappa B, as well as the translocation of the p65 subunit of NF-kappa B to the nucleus and increased expression of an NF-kappa B-dependent reporter gene. Inhibitors of the p38, ERK, or Akt pathways each partially reduced CT-1-mediated NF-kappa B activation, as well as the cytoprotective effects of CT-1 against hypoxic stress. Together, the inhibitors completely blocked CT-1-dependent NF-kappa B activation and cytoprotection. A cell-permeable peptide that selectively disrupted NF-kappa B activation also completely inhibited the cytoprotective effects of CT-1. These results indicate that CT-1 signals through p38, ERK, and Akt in a parallel manner to activate NF-kappa B and that NF-kappa B is required for CT-1 to mediate its full cytoprotective effects in cardiac myocytes.},
	address = {United States},
	article-doi = {10.1074/jbc.M103276200},
	article-pii = {S0021-9258(19)56711-4},
	author = {Craig, R. and Wagner, M. and McCardle, T. and Craig, A. G. and Glembotski, C. C.},
	completed = {20011204},
	electronic-publication = {20010711},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {2001/07/13 10:00 [entrez]},
	issue = {40},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Biological Transport/drug effects, Cell Hypoxia, Cells, Cultured, Cytokines/*pharmacology, Enzyme Activation/drug effects, I-kappa B Proteins/metabolism, Mitogen-Activated Protein Kinases/metabolism, Myocardium/cytology/*metabolism, NF-kappa B/genetics/*metabolism, Phosphatidylinositol 3-Kinases/metabolism, Protective Agents/pharmacology, Rats, Rats, Sprague-Dawley, Signal Transduction, Transcription, Genetic/drug effects, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Oct},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {37621--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)},
	revised = {20210209},
	source = {J Biol Chem. 2001 Oct 5;276(40):37621-9. doi: 10.1074/jbc.M103276200. Epub 2001 Jul 11.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The cytoprotective effects of the glycoprotein 130 receptor-coupled cytokine, cardiotrophin-1, require activation of NF-kappa B.},
	title-abbreviation = {J Biol Chem},
	volume = {276},
	year = {2001}
}

@article{Ho_2001_CircRes_88_63,
	abstract = {Heart failure is associated with dysregulation of intracellular calcium ([Ca(2+)](i)), reduction in myofibrils, and increased activation of Ras, a regulator of signal-transduction pathways. To evaluate the potential effects of Ras on [Ca(2+)](i), we expressed constitutively active Ras (Ha-Ras(V12)) in cardiac myocytes and monitored [Ca(2+)](i) via fluorescence and electrophysiological techniques. Ha-Ras(V12) reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-Ras(V12) introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-Ras(V12), which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-Ras(V12)-induced dysregulation of [Ca(2+)](i). Furthermore, whereas Ha-Ras(V12) downregulated myofibrils, this effect was blocked by coexpression of L-channels. These results suggest that Ras downregulates L-channel expression, which may play a pathophysiological role in cardiac disease.},
	address = {United States},
	article-doi = {10.1161/01.res.88.1.63},
	author = {Ho, P. D. and Fan, J. S. and Hayes, N. L. and Saada, N. and Palade, P. T. and Glembotski, C. C. and McDonough, P. M.},
	completed = {20010301},
	electronic-issn = {1524-4571},
	grantno = {etc.},
	history = {2001/01/05 11:00 [entrez]},
	issue = {1},
	journal = {Circulation research},
	keywords = {Animals, Caffeine/pharmacology, Calcium/metabolism, Calcium Channels, L-Type/genetics/*physiology, Calcium-Transporting ATPases/genetics/metabolism, Cell Size, Cells, Cultured, Heart Ventricles/cytology/drug effects, Luciferases/genetics/metabolism, Membrane Potentials/drug effects, Myofibrils/metabolism, Patch-Clamp Techniques, Potassium Chloride/pharmacology, Promoter Regions, Genetic/genetics, Rats, Recombinant Fusion Proteins/genetics/metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases, *Ventricular Function, ras Proteins/genetics/*physiology},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Jan},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {63--9},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20191210},
	source = {Circ Res. 2001 Jan 19;88(1):63-9. doi: 10.1161/01.res.88.1.63.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Ras reduces L-type calcium channel current in cardiac myocytes. Corrective effects of L-channels and SERCA2 on [Ca(2+)](i) regulation and cell morphology.},
	title-abbreviation = {Circ Res},
	volume = {88},
	year = {2001}
}

@article{Nakajima_2000_Europeanjournalofbiochemistry_267_5679,
	abstract = {Recent evidence indicates that sphingolipids are produced by the heart during hypoxic stress and by blood platelets during thrombus formation. It is therefore possible that sphingolipids may influence heart cell function by interacting with G-protein-coupled receptors of the Edg family. In the present study, it was found that sphingosine 1-phosphate (Sph1P), the prototypical ligand for Edg receptors, produced calcium overload in rat cardiomyocytes. The cDNA for Edg-1 was cloned from rat cardiomyocytes and, when transfected in an antisense orientation, effectively blocked Edg-1 protein expression and reduced the Sph1P-mediated calcium deregulation. Taken together, these results demonstrate that cardiomyocytes express an extracellular lipid-sensitive receptorsystem that can respond to sphingolipid mediators. Because the major source of Sph1P is from blood platelets, we speculate that Edg-mediated Sph1P negative inotropic and cardiotoxic effects may play important roles in acute myocardial ischemia where Sph1P levels are probably elevated in response to thrombus.},
	address = {England},
	article-doi = {10.1046/j.1432-1327.2000.01656.x},
	article-pii = {ejb1656},
	author = {Nakajima, N. and Cavalli, A. L. and Biral, D. and Glembotski, C. C. and McDonough, P. M. and Ho, P. D. and Betto, R. and Sandon{\'a}, D. and Palade, P. T. and Dettbarn, C. A. and Klepper, R. E. and Sabbadini, R. A.},
	completed = {20001107},
	grantno = {NS/HL 25037/NS/NINDS NIH HHS/United States},
	history = {2000/09/06 11:00 [entrez]},
	issue = {18},
	journal = {European journal of biochemistry},
	keywords = {Animals, Blood Platelets/metabolism, Blotting, Western, Calcium/*metabolism, Cardiac Pacing, Artificial, Cells, Cultured, Cloning, Molecular, DNA, Complementary/metabolism, Green Fluorescent Proteins, Immediate-Early Proteins/*biosynthesis/*genetics, Ligands, Luminescent Proteins/metabolism, *Lysophospholipids, Myocardium/*metabolism, Oligonucleotides, Antisense/genetics, Plasmids/metabolism, Rats, *Receptors, Cell Surface, *Receptors, G-Protein-Coupled, Receptors, Lysophospholipid, Reverse Transcriptase Polymerase Chain Reaction, Sarcoplasmic Reticulum/metabolism, Signal Transduction, Sphingosine/*analogs \& derivatives/genetics/*metabolism/*pharmacology, Time Factors, Transfection},
	language = {eng},
	linking-issn = {0014-2956},
	month = {Sep},
	nlm-unique-id = {0107600},
	owner = {NLM},
	pages = {5679--86},
	print-issn = {0014-2956},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20190620},
	source = {Eur J Biochem. 2000 Sep;267(18):5679-86. doi: 10.1046/j.1432-1327.2000.01656.x.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Expression and characterization of Edg-1 receptors in rat cardiomyocytes: calcium deregulation in response to sphingosine 1-phosphate.},
	title-abbreviation = {Eur J Biochem},
	volume = {267},
	year = {2000}
}

@article{Morissette_2000_AmJPhysiolHeartCircPhysiol_278_H1769,
	abstract = {The low-molecular-weight GTP-binding protein RhoA mediates hypertrophic growth and atrial natriuretic factor (ANF) gene expression in neonatal rat ventricular myocytes. Neither the effector nor the promoter elements through which Rho exerts its regulatory effects on ANF gene expression have been elucidated. When constitutively activated forms of Rho kinase and two protein kinase C-related kinases, PKN (PRK1) and PRK2, were compared, only PKN generated a robust stimulation of a luciferase reporter gene driven by a 638-bp fragment on the ANF promoter. This ANF promoter fragment contains a proximal serum response element (SRE) and an Sp-1-like element required for the transcriptional response to phenylephrine (PE). This response was inhibited by dominant negative Rho. The ability of dominant negative Rho to inhibit the response to PE and the ability of PKN to stimulate ANF reporter gene expression were both lost when the SRE was mutated. Mutation of the Sp-1-like element also attenuated the response to PKN. A minimal promoter driven by ANF SRE sequences was sufficient to confer Rho- and PKN-mediated gene expression. Interestingly, PKN preferentially stimulated the ANF versus the c-fos SRE reporter gene. Thus PKN and Rho are able to regulate transcriptional activation of the ANF SRE by a common element that could implicate PKN as a downstream effector of Rho in transcriptional responses associated with hypertrophy.},
	address = {United States},
	article-doi = {10.1152/ajpheart.2000.278.6.H1769},
	author = {Morissette, M. R. and Sah, V. P. and Glembotski, C. C. and Brown, J. H.},
	completed = {20000713},
	grantno = {HL-46345/HL/NHLBI NIH HHS/United States},
	history = {2000/06/14 09:00 [entrez]},
	issue = {6},
	journal = {American journal of physiology. Heart and circulatory physiology},
	keywords = {Animals, Atrial Natriuretic Factor/*genetics, *Blood Physiological Phenomena, Gene Expression/physiology, Heart/*physiology, Intracellular Signaling Peptides and Proteins, Protein Kinase C/*physiology, Protein-Serine-Threonine Kinases/physiology, Proto-Oncogene Proteins c-fos/genetics, Rats, Rats, Sprague-Dawley, Response Elements/*physiology, Transcription, Genetic/*physiology, Transcriptional Activation/physiology, rho-Associated Kinases},
	language = {eng},
	linking-issn = {0363-6135},
	month = {Jun},
	nlm-unique-id = {100901228},
	owner = {NLM},
	pages = {H1769--74},
	print-issn = {0363-6135},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.13 (Protein Kinase C)},
	revised = {20200930},
	source = {Am J Physiol Heart Circ Physiol. 2000 Jun;278(6):H1769-74. doi: 10.1152/ajpheart.2000.278.6.H1769.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element.},
	title-abbreviation = {Am J Physiol Heart Circ Physiol},
	volume = {278},
	year = {2000}
}

@article{Hoover_2000_JBiolChem_275_23825,
	abstract = {The MAPK kinase MKK6 selectively stimulates p38 MAPK and confers protection against stress-induced apoptosis in cardiac myocytes. However, the events lying downstream of p38 that mediate this protection are unknown. The small heat shock protein, alphaB-crystallin, which is expressed in only a few cell types, including cardiac myocytes, may participate in MKK6-mediated cytoprotection. In the present study, we showed that, in cultured cardiac myocytes, expression of MKK6(Glu), an active form of MKK6, led to p38-dependent increases in alphaB-crystallin mRNA, protein, and transcription. MKK6(Glu) also induced p38-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2, and the phosphorylation of alphaB-crystallin on serine-59. Initially, exposure of cells to the hyperosmotic stressor, sorbitol, stimulated MKK6, p38, and MAPKAP-K2 and increased phosphorylation of alphaB-crystallin on serine 59. However, after longer times of exposure to sorbitol, the cells began to undergo apoptosis. This sorbitol-induced apoptosis was increased when p38 was inhibited in a manner that would block alphaB-crystallin induction and phosphorylation. Thus, under these conditions, the activation of MKK6, p38, and MAPKAP-K2 by sorbitol can provide a degree of protection against stress-induced apoptosis. Supporting this view was the finding that sorbitol-induced apoptosis was nearly completely blocked in cells expressing MKK6(Glu). Therefore, the cytoprotective effects of MKK6 in cardiac myocytes are due, in part, to phosphorylation of alphaB-crystallin on serine 59 and to the induction of alphaB-crystallin gene expression.},
	address = {United States},
	article-doi = {10.1074/jbc.M003864200},
	article-pii = {S0021-9258(19)66047-3},
	author = {Hoover, H. E. and Thuerauf, D. J. and Martindale, J. J. and Glembotski, C. C.},
	completed = {20000907},
	grantno = {etc.},
	history = {2000/05/19 09:00 [entrez]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Apoptosis, Arsenites/pharmacology, Calcium-Calmodulin-Dependent Protein Kinases/*metabolism, Cells, Cultured/drug effects, Crystallins/biosynthesis/*genetics, DNA-Binding Proteins, Enzyme Activation, Gene Expression Regulation, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 6, Mitogen-Activated Protein Kinases/*metabolism, Myocardium/cytology/*metabolism, Nuclear Proteins, Phosphorylation, Protective Agents, Protein-Serine-Threonine Kinases/metabolism, Rats, Rats, Sprague-Dawley, Response Elements, Serum Response Factor, Signal Transduction, Sorbitol/pharmacology, Stress, Physiological/*metabolism, Transcriptional Activation, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {23825--33},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {N5509X556J (arsenite)},
	revised = {20210209},
	source = {J Biol Chem. 2000 Aug 4;275(31):23825-33. doi: 10.1074/jbc.M003864200.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response.},
	title-abbreviation = {J Biol Chem},
	volume = {275},
	year = {2000}
}

@article{Craig_2000_JBiolChem_275_23814,
	abstract = {In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.},
	address = {United States},
	article-doi = {10.1074/jbc.M909695199},
	article-pii = {S0021-9258(19)66046-1},
	author = {Craig, R. and Larkin, A. and Mingo, A. M. and Thuerauf, D. J. and Andrews, C. and McDonough, P. M. and Glembotski, C. C.},
	completed = {20000907},
	grantno = {etc.},
	history = {2000/04/27 09:00 [entrez]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, *Autocrine Communication, Biological Transport, Calcium-Calmodulin-Dependent Protein Kinases/metabolism, DNA-Binding Proteins/metabolism, Gene Expression Regulation, I-kappa B Kinase, Interleukin-6/*genetics/metabolism, MAP Kinase Kinase 6, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases/*metabolism, Models, Biological, Myocardium/cytology/*metabolism, NF-kappa B/antagonists \& inhibitors/*metabolism, Phosphorylation, Protective Agents, Protein-Serine-Threonine Kinases/metabolism, Rats, Rats, Sprague-Dawley, Receptor Cross-Talk, STAT3 Transcription Factor, Trans-Activators/metabolism, Transcription, Genetic, Tumor Necrosis Factor-alpha/pharmacology, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {23814--24},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.7.12.2 (MAP Kinase Kinase 6)},
	revised = {20210209},
	source = {J Biol Chem. 2000 Aug 4;275(31):23814-24. doi: 10.1074/jbc.M909695199.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system.},
	title-abbreviation = {J Biol Chem},
	volume = {275},
	year = {2000}
}

@article{Comstock_1998_JMolCellCardiol_30_2761,
	abstract = {The bacterial endotoxin lipopolysaccharide (LPS) contributes to the cardiovascular collapse and death observed in patients with sepsis. Because LPS has such profound effects on cardiac performance, we speculate that direct effects of LPS could be demonstrated on cardiomyocytes in culture, and that these direct effects are mediated by the LPS receptor, CD14. Accordingly, in this study, we provide evidence for CD14-dependent cardiotoxic effects of LPS including the LPS-stimulated secretion of tumor necrosis factor alpha (TNF-alpha) from cardiomyocytes. TNF-alpha is an inflammatory cytokine which is known for its negative inotropic effects on cardiac performance, but has not until recently been shown to be produced by cardiac cells. In this study, LPS was found to stimulate strongly in a dose-dependent manner the secretion of TNF-alpha from cultured adult rat cardiomyocytes. Further, LPS-induced TNF-alpha secretion was blocked by an inhibitor of TNF-alpha processing, metallomatrix protease inhibitor (TAPI). Molecular and immunological evidence demonstrated the presence of LPS receptors (CD14) on cardiomyocytes. Attenuated TNF-alpha secretion following PI-PLC treatment confirmed the functional importance of CD14 for LPS-mediated myocardial effects. Importantly, LPS also triggered apoptosis in cultured cardiomyocytes as quantified by single-cell gel electrophoresis of nuclei exhibiting DNA fragmentation patterns characteristic of apoptosis (i.e. cardiac comets). Apoptotic cell death was blocked by pre-incubation with the soluble TNF-alpha receptor fragment (TNFRII:Fc), suggesting that LPS-induced apoptosis was TNF-alpha-dependent and probably involved an autocrine function for the TNF-alpha whose secretion was under LPS control. The results of this study suggest that the cardiodepressant effects of LPS are dependent on CD14 signaling and may not only be due to acute negative inotropic effects of TNF-alpha but also may be complicated by TNF-alpha-induced apoptotic cell death which effectively reduces the number of working myocardial cells.},
	address = {England},
	article-doi = {10.1006/jmcc.1998.0851},
	article-pii = {S0022-2828(98)90851-3},
	author = {Comstock, K. L. and Krown, K. A. and Page, M. T. and Martin, D. and Ho, P. and Pedraza, M. and Castro, E. N. and Nakajima, N. and Glembotski, C. C. and Quintana, P. J. and Sabbadini, R. A.},
	completed = {19990430},
	grantno = {HL 46345/HL/NHLBI NIH HHS/United States},
	history = {1999/02/17 00:00 [entrez]},
	issue = {12},
	journal = {Journal of molecular and cellular cardiology},
	keywords = {Animals, Apoptosis/*physiology, Blotting, Western, Calcium/metabolism, Dose-Response Relationship, Drug, Electrophoresis, Gel, Two-Dimensional, Enzyme-Linked Immunosorbent Assay, Heart/*physiology, Lipopolysaccharide Receptors/*physiology, Lipopolysaccharides/*pharmacology, Male, Models, Biological, Muscle, Skeletal/drug effects, Necrosis, Phenylephrine/pharmacology, Phosphatidylinositol Diacylglycerol-Lyase, Phosphoinositide Phospholipase C, Polymerase Chain Reaction, Protease Inhibitors/pharmacology, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha/*metabolism/physiology, Type C Phospholipases/pharmacology, Tyrphostins/pharmacology},
	language = {eng},
	linking-issn = {0022-2828},
	month = {Dec},
	nlm-unique-id = {0262322},
	owner = {NLM},
	pages = {2761--75},
	print-issn = {0022-2828},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20171116},
	source = {J Mol Cell Cardiol. 1998 Dec;30(12):2761-75. doi: 10.1006/jmcc.1998.0851.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {LPS-induced TNF-alpha release from and apoptosis in rat cardiomyocytes: obligatory role for CD14 in mediating the LPS response.},
	title-abbreviation = {J Mol Cell Cardiol},
	volume = {30},
	year = {1998}
}

@article{Ho_1998_JBiolChem_273_21730,
	abstract = {Ras and protein kinase C (PKC), which regulate the Raf-MEK-ERK cascade, may participate in the development of cardiac hypertrophy, a condition characterized by diminished and prolonged contractile calcium transients. To directly examine the influence of this pathway on intracellular calcium ([Ca2+]i), cardiac myocytes were cotransfected with effectors of this pathway and with green fluorescent protein, which allowed the living transfected myocytes to be identified and examined for [Ca2+]i via indo-1. Transfection with constitutively active Ras (Ha-RasV12) increased cell size, decreased expression of the myofibrils and the calcium-regulatory enzyme SERCA2, and reduced the magnitude and prolonged the decay phase of the contractile [Ca2+]i transients. Similar effects on [Ca2+]i were obtained with Ha-RasV12S35, a Ras mutant that selectively couples to Raf, and with constitutively active Raf. In contrast, Ha-RasV12C40, a Ras mutant that activates the phosphatidylinositol 3-kinase pathway, had a lesser effect. The PKC-activating phorbol ester, phorbol 12-myristate 13-acetate, also prolonged the contractile [Ca2+]i transients. Cotransfection with dnMEK inhibited the effects of Ha-RasV12, Raf, and phorbol 12-myristate 13-acetate on [Ca2+]i. The effects of Ha-RasV12 and Raf on [Ca2+]i were also counteracted by SERCA2 overexpression. Both Ras and PKC may thus regulate cardiac [Ca2+]i via the Raf-MEK-ERK cascade, and this pathway may represent a critical determinant of cardiac physiological function.},
	address = {United States},
	article-doi = {10.1074/jbc.273.34.21730},
	article-pii = {S0021-9258(18)48844-8},
	author = {Ho, P. D. and Zechner, D. K. and He, H. and Dillmann, W. H. and Glembotski, C. C. and McDonough, P. M.},
	completed = {19980917},
	grantno = {etc.},
	history = {1998/08/15 00:00 [entrez]},
	issue = {34},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Calcium/*metabolism, Calcium-Calmodulin-Dependent Protein Kinases/*metabolism, Calcium-Transporting ATPases/metabolism, Cells, Cultured, MAP Kinase Kinase 6, Myocardium/*metabolism, Protein Kinase C/*metabolism, Protein-Serine-Threonine Kinases/metabolism, Rats, ras Proteins/*metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {21730--5},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210209},
	source = {J Biol Chem. 1998 Aug 21;273(34):21730-5. doi: 10.1074/jbc.273.34.21730.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The Raf-MEK-ERK cascade represents a common pathway for alteration of intracellular calcium by Ras and protein kinase C in cardiac myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {273},
	year = {1998}
}

@article{Thuerauf_1998_JBiolChem_273_20636,
	abstract = {In various cell types certain stresses can stimulate p38 mitogen-activated protein kinase (p38 MAPK), leading to the transcriptional activation of genes that contribute to appropriate compensatory responses. In this report the mechanism of p38-activated transcription was studied in cardiac myocytes where this MAPK is a key regulator of the cell growth and the cardiac-specific gene induction that occurs in response to potentially stressful stimuli. In the cardiac atrial natriuretic factor (ANF) gene, a promoter-proximal serum response element (SRE), which binds serum response factor (SRF), was shown to be critical for ANF induction in primary cardiac myocytes transfected with the selective p38 MAPK activator, MKK6 (Glu). This ANF SRE does not possess sequences typically required for the binding of the Ets-related ternary complex factors (TCFs), such as Elk-1, indicating that p38-mediated induction through this element may take place independently of such TCFs. Although p38 did not phosphorylate SRF in vitro, it efficiently phosphorylated ATF6, a newly discovered SRF-binding protein that is believed to serve as a co-activator of SRF-inducible transcription at SREs. Expression of an ATF6 antisense RNA blocked p38-mediated ANF induction through the ANF SRE. Moreover, when fused to the Gal4 DNA-binding domain, an N-terminal 273-amino acid fragment of ATF6 was sufficient to support trans-activation of Gal4/luciferase expression in response to p38 but not the other stress kinase, N-terminal Jun kinase (JNK); p38-activating cardiac growth promoters also stimulated ATF6 trans-activation. These results indicate that through ATF6, p38 can augment SRE-mediated transcription independently of Ets-related TCFs, representing a novel mechanism of SRF-dependent transcription by MAP kinases.},
	address = {United States},
	article-doi = {10.1074/jbc.273.32.20636},
	article-pii = {S0021-9258(18)49101-6},
	author = {Thuerauf, D. J. and Arnold, N. D. and Zechner, D. and Hanford, D. S. and DeMartin, K. M. and McDonough, P. M. and Prywes, R. and Glembotski, C. C.},
	completed = {19980910},
	grantno = {etc.},
	history = {1998/08/01 00:00 [entrez]},
	issue = {32},
	journal = {The Journal of biological chemistry},
	keywords = {Activating Transcription Factor 6, Animals, Atrial Natriuretic Factor/*genetics, Calcium-Calmodulin-Dependent Protein Kinases/*physiology, Cells, Cultured, DNA-Binding Proteins/analysis/genetics/metabolism, Endothelin-1/pharmacology, Gene Expression Regulation/*genetics, *Mitogen-Activated Protein Kinases, Myocardium/*enzymology, Nuclear Proteins/genetics, Phenylephrine/pharmacology, Phosphorylation, Promoter Regions, Genetic/genetics, Protein-Serine-Threonine Kinases/metabolism, RNA, Antisense/pharmacology, Rats, Recombinant Fusion Proteins/metabolism, Serum Response Factor, Transcription Factors/genetics/metabolism, Transcriptional Activation/drug effects/physiology, Transfection/genetics, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {20636--43},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)},
	revised = {20210209},
	source = {J Biol Chem. 1998 Aug 7;273(32):20636-43. doi: 10.1074/jbc.273.32.20636.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {p38 Mitogen-activated protein kinase mediates the transcriptional induction of the atrial natriuretic factor gene through a serum response element. A potential role for the transcription factor ATF6.},
	title-abbreviation = {J Biol Chem},
	volume = {273},
	year = {1998}
}

@article{Ross_1998_CircRes_82_1160,
	abstract = {Multiple signaling pathways have been implicated in the hypertrophic response of ventricular myocytes, yet the importance of cell-matrix interactions has not been extensively examined. Integrins are cell-surface molecules that link the extracellular matrix to the cellular cytoskeleton. They can function as cell signaling molecules and transducers of mechanical information in noncardiac cells. Given these properties and their abundance in cardiac cells, we evaluated the hypothesis that beta1 integrin function is involved in the alpha1-adrenergic mediated hypertrophic response of neonatal rat ventricular myocytes. The hypertrophic response of this model required interaction with extracellular matrix proteins. Specificity of these results was confirmed by demonstrating that ventricular myocytes plated onto an anti-beta1 integrin antibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of beta1 integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic factor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed beta1A integrin or the cardiac/skeletal muscle-specific beta1 isoform (beta1D) activated reporter expression from both the atrial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ventricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free beta1 integrin cytoplasmic domains inhibited the adrenergically mediated atrial natriuretic factor response. These findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway.},
	address = {United States},
	article-doi = {10.1161/01.res.82.11.1160},
	author = {Ross, R. S. and Pham, C. and Shai, S. Y. and Goldhaber, J. I. and Fenczik, C. and Glembotski, C. C. and Ginsberg, M. H. and Loftus, J. C.},
	completed = {19980702},
	grantno = {HL-57872/HL/NHLBI NIH HHS/United States},
	history = {1998/06/20 00:00 [entrez]},
	issue = {11},
	journal = {Circulation research},
	keywords = {Adenoviridae, Adrenergic alpha-Agonists/pharmacology, Animals, Animals, Newborn, Atrial Natriuretic Factor/analysis, Cardiomegaly/pathology/*physiopathology, Extracellular Matrix/chemistry/metabolism, Gene Expression Regulation, Viral/physiology, Heart Ventricles/chemistry/pathology, Integrin beta1/chemistry/*genetics/metabolism, Isomerism, Myocardium/*chemistry/pathology, Phenylephrine/pharmacology, Promoter Regions, Genetic/drug effects/physiology, Rats, Rats, Sprague-Dawley, Signal Transduction/*physiology, Transfection},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Jun},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1160--72},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190706},
	source = {Circ Res. 1998 Jun 15;82(11):1160-72. doi: 10.1161/01.res.82.11.1160.},
	status = {MEDLINE},
	subset = {S},
	timestamp = {2021.09.20},
	title = {Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes.},
	title-abbreviation = {Circ Res},
	volume = {82},
	year = {1998}
}

@article{Zechner_1998_JBiolChem_273_8232,
	abstract = {In cardiac myocytes the stimulation of p38 mitogen-activated protein kinase activates a hypertrophic growth program and the induction of the cardiac-specific genes associated with this program. This study focused on determining whether these novel growth-promoting effects are accompanied by the p38-mediated inhibition of apoptosis, and if so, what signaling pathways might be responsible. Primary neonatal rat ventricular myocytes were driven into apoptosis by treatments known to induce apoptosis in other cell types, e.g. incubation with anisomycin or overexpression constitutively active MEKK-1 (MEKK-1COOH), a protein that strongly activates extracellular signal-regulated kinase and N-terminal c-Jun kinase, but not p38. Overexpression of constitutively active MKK6, MKK6 (Glu), which selectively activates p38 in cardiac myocytes, protected cells from either anisomycin- or MEKK-1COOH-induced apoptosis. This protection was blocked by SB 203580, a selective p38 inhibitor. MKK6 (Glu) also activated transcription mediated by NF-kappaB, a factor which protects other cell types from apoptosis. The activation of NF-kappaB and the protection from apoptosis mediated by MKK6 (Glu) were both blocked by SB 203580. Interestingly, overexpression of a mutant form of I-kappaBalpha, which inhibits nuclear translocation of NF-kappaB, completely blocked MKK6 (Glu)-activated NF-kappaB but had little effect on MKK6s anti-apoptotic effects. These findings suggest that, in part, the overexpression of MKK6 (Glu) may foster growth and survival of cardiac myocytes by protecting them from apoptosis in a p38-dependent manner. Additionally, while NF-kappaB is activated in myocardial cells by p38, this does not appear to be the major mechanism by which MKK6 (Glu) exerts its anti-apoptotic effects in this cell type, suggesting a novel pathway for p38-mediated protection from apoptosis.},
	address = {United States},
	article-doi = {10.1074/jbc.273.14.8232},
	article-pii = {S0021-9258(18)52550-3},
	author = {Zechner, D. and Craig, R. and Hanford, D. S. and McDonough, P. M. and Sabbadini, R. A. and Glembotski, C. C.},
	completed = {19980507},
	grantno = {etc.},
	history = {1998/05/09 00:00 [entrez]},
	issue = {14},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, *Apoptosis/genetics, Calcium-Calmodulin-Dependent Protein Kinases/*metabolism, Cells, Cultured, Gene Expression Regulation, Gene Transfer Techniques, MAP Kinase Kinase 6, *Mitogen-Activated Protein Kinases, Myocardium/*metabolism/pathology, NF-kappa B/genetics/*metabolism, Rats, *Signal Transduction/genetics, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Apr},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {8232--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.7.12.2 (MAP Kinase Kinase 6)},
	revised = {20210209},
	source = {J Biol Chem. 1998 Apr 3;273(14):8232-9. doi: 10.1074/jbc.273.14.8232.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {MKK6 activates myocardial cell NF-kappaB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner.},
	title-abbreviation = {J Biol Chem},
	volume = {273},
	year = {1998}
}

@article{Zechner_1997_JCellBiol_139_115,
	abstract = {Three hallmark features of the cardiac hypertrophic growth program are increases in cell size, sarcomeric organization, and the induction of certain cardiac-specific genes. All three features of hypertrophy are induced in cultured myocardial cells by alpha1- adrenergic receptor agonists, such as phenylephrine (PE) and other growth factors that activate mitogen- activated protein kinases (MAPKs). In this study the MAPK family members extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and p38 were activated by transfecting cultured cardiac myocytes with constructs encoding the appropriate kinases possessing gain-of-function mutations. Transfected cells were then analyzed for changes in cell size, sarcomeric organization, and induction of the genes for the A- and B-type natriuretic peptides (NPs), as well as the alpha-skeletal actin (alpha-SkA) gene. While activation of JNK and/or ERK with MEKK1COOH or Raf-1 BXB, respectively, augmented cell size and effected relatively modest increases in NP and alpha-SkA promoter activities, neither upstream kinase conferred sarcomeric organization. However, transfection with MKK6 (Glu), which specifically activated p38, augmented cell size, induced NP and alpha-Ska promoter activities by up to 130-fold, and elicited sarcomeric organization in a manner similar to PE. Moreover, all three growth features induced by MKK6 (Glu) or PE were blocked with the p38-specific inhibitor, SB 203580. These results demonstrate novel and potentially central roles for MKK6 and p38 in the regulation of myocardial cell hypertrophy.},
	article-doi = {10.1083/jcb.139.1.115},
	author = {Zechner, D. and Thuerauf, D. J. and Hanford, D. S. and McDonough, P. M. and Glembotski, C. C.},
	completed = {19980218},
	electronic-issn = {1540-8140},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {1997/10/06 00:00 [entrez]},
	issue = {1},
	journal = {The Journal of cell biology},
	keywords = {Animals, Calcium-Calmodulin-Dependent Protein Kinases/antagonists \& inhibitors/*physiology, Cardiomegaly/enzymology/genetics/pathology, Cell Division/drug effects/genetics, Cell Size/genetics, Cells, Cultured, Enzyme Inhibitors/pharmacology, *Gene Expression Regulation/drug effects, Imidazoles/pharmacology, MAP Kinase Kinase 6, *Mitogen-Activated Protein Kinases, Myocardium/cytology/*enzymology/*metabolism, Phenylephrine/pharmacology, Pyridines/pharmacology, Rats, Sarcomeres/drug effects/enzymology/*physiology, p38 Mitogen-Activated Protein Kinases},
	language = {eng},
	linking-issn = {0021-9525},
	month = {Oct},
	nlm-unique-id = {0375356},
	owner = {NLM},
	pages = {115--27},
	print-issn = {0021-9525},
	publication-status = {ppublish},
	registry-number = {OU13V1EYWQ (SB 203580)},
	revised = {20191023},
	source = {J Cell Biol. 1997 Oct 6;139(1):115-27. doi: 10.1083/jcb.139.1.115.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression.},
	title-abbreviation = {J Cell Biol},
	volume = {139},
	year = {1997}
}

@article{McDonough_1997_JBiolChem_272_24046,
	abstract = {Electrical stimulation of contractions (pacing) of primary neonatal rat ventricular myocytes increases intracellular calcium and activates a hypertrophic growth program that includes expression of the cardiac-specific gene, atrial natriuretic factor (ANF). To investigate the mechanism whereby pacing increases ANF, pacing was tested for its ability to regulate mitogen-activated protein kinase family members, ANF promoter activity, and the trans-activation domain of the transcription factor, Sp1. Pacing and the calcium channel agonist BAYK 8644 activated c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated kinase. Pacing stimulated ANF-promoter activity approximately 10-fold. Furthermore, transfection with an expression vector for c-Jun, a substrate for JNK, also activated the ANF promoter, and the combination of pacing and c-Jun was synergystic, consistent with roles for JNK and c-Jun in calcium-activated ANF expression. Proximal serum response factor and Sp1 binding sites were required for the effects of pacing or c-Jun on the ANF promoter. Pacing and c-Jun activated a GAL4-Sp1 fusion protein by 3- and 12-fold, respectively, whereas the two stimuli together activated GAL4-Sp1 synergistically, similar to their effect on the ANF promoter. Transfection with an expression vector for c-Fos inhibited the effects of c-Jun, suggesting that c-Jun acts independently of AP-1. These results demonstrate an interaction between c-Jun and Sp1 and are consistent with a novel mechanism of calcium-mediated transcriptional activation involving the collaborative actions of JNK, c-Jun, serum response factor, and Sp1.},
	address = {United States},
	article-doi = {10.1074/jbc.272.38.24046},
	article-pii = {S0021-9258(19)65890-4},
	author = {McDonough, P. M. and Hanford, D. S. and Sprenkle, A. B. and Mellon, N. R. and Glembotski, C. C.},
	completed = {19971023},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {1997/09/20 00:00 [entrez]},
	issue = {38},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Atrial Natriuretic Factor/genetics, Calcium/*metabolism, Calcium-Calmodulin-Dependent Protein Kinases/*metabolism, Cells, Cultured, DNA-Binding Proteins/*metabolism, *Gene Expression Regulation, Heart Ventricles/cytology/*metabolism, JNK Mitogen-Activated Protein Kinases, *Mitogen-Activated Protein Kinases, Nuclear Proteins/*metabolism, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun/*metabolism, Rats, Serum Response Factor, Sp1 Transcription Factor/*metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Sep},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {24046--53},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210209},
	source = {J Biol Chem. 1997 Sep 19;272(38):24046-53. doi: 10.1074/jbc.272.38.24046.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Collaborative roles for c-Jun N-terminal kinase, c-Jun, serum response factor, and Sp1 in calcium-regulated myocardial gene expression.},
	title-abbreviation = {J Biol Chem},
	volume = {272},
	year = {1997}
}

@article{Thuerauf_1997_JBiolChem_272_7464,
	abstract = {The cardiac genes for the A- and B-type natriuretic peptides (ANP and BNP) are coordinately induced by growth promoters, such as alpha1-adrenergic receptor agonists (e.g. phenylephrine (PE)). Although inducible elements in the ANP gene have been identified, responsible elements in the BNP gene are unknown. In this study, reporter constructs transfected into neonatal rat ventricular myocytes showed that in the context of 2.5 kilobase pairs of native BNP 5'-flanking sequences, a 2-base pair mutation in a promoter-proximal M-CAT site (CATTCT) disrupted basal and PE-inducible transcription by more than 98\%. Expression of constitutively active forms of Ras, Raf-1 kinase, and protein kinase C, all of which are activated by PE in cardiac myocytes, strongly stimulated BNP reporter expression. Isolated M-CAT elements conferred PE, protein kinase C, and Ras inducibility to a minimal BNP promoter, however, they did not confer Raf-1 inducibility. These results show that M-CAT elements can serve as targets for Ras-dependent, Raf-1-independent pathways, implying the involvement of c-Jun N-terminal kinase and/or p38 mitogen-activated protein kinases, but not extracellular signal-regulated protein kinase/mitogen-activated protein kinase. Moreover, the essential M-CAT element distinguishes the BNP gene from the ANP gene, which utilizes serum response elements and an Sp1-like sequence.},
	address = {United States},
	article-doi = {10.1074/jbc.272.11.7464},
	article-pii = {S0021-9258(18)41089-7},
	author = {Thuerauf, D. J. and Glembotski, C. C.},
	completed = {19970417},
	grantno = {NS-25073/NS/NINDS NIH HHS/United States},
	history = {1997/03/14 00:00 [entrez]},
	issue = {11},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Atrial Natriuretic Factor/biosynthesis/*genetics, Base Sequence, Cells, Cultured, *Gene Expression Regulation, Heart Ventricles/*metabolism, Molecular Sequence Data, Oligonucleotides, Promoter Regions, Genetic/genetics, Protein Kinase C/*genetics/metabolism, Protein-Serine-Threonine Kinases/*genetics/metabolism, Proto-Oncogene Proteins/*genetics/metabolism, Proto-Oncogene Proteins c-raf, Rats, ras Proteins/*genetics/metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Mar},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7464--72},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.6.5.2 (ras Proteins)},
	revised = {20210209},
	source = {J Biol Chem. 1997 Mar 14;272(11):7464-72. doi: 10.1074/jbc.272.11.7464.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Differential effects of protein kinase C, Ras, and Raf-1 kinase on the induction of the cardiac B-type natriuretic peptide gene through a critical promoter-proximal M-CAT element.},
	title-abbreviation = {J Biol Chem},
	volume = {272},
	year = {1997}
}

@article{Betto_1997_BiochemJ_322Pt1_327,
	abstract = {Sphingosylphosphocholine (SPC) modulates Ca2+ release from isolated cardiac sarcoplasmic reticulum membranes; 50 microM SPC induces the release of 70 80\% of the accumulated calcium. SPC release calcium from cardiac sarcoplasmic reticulum through the ryanodine receptor, since the release is inhibited by the ryanodine receptor channel antagonists ryanodine. Ruthenium Red and sphingosine. In intact cardiac myocytes, even in the absence of extracellular calcium. SPC causes a rise in diastolic Ca2+, which is greatly reduced when the sarcoplasmic reticulum is depleted of Ca2+ by prior thapsigargin treatment. SPC action on the ryanodine receptor is Ca(2+)-dependent. SPC shifts to the left the Ca(2+)-dependence of [3H]ryanodine binding, but only at high pCa values, suggesting that SPC might increase the sensitivity to calcium of the Ca(2+)-induced Ca(2+)-release mechanism. At high calcium concentrations (pCa 4.0 or lower), where [3H]ryanodine binding is maximally stimulated, no effect of SPC is observed. We conclude that SPC releases calcium from cardiac sarcoplasmic reticulum membranes by activating the ryanodine receptor and possibly another intracellular Ca(2+)-release channel, the sphingolipid Ca(2+)-release-mediating protein of endoplasmic reticulum (SCaMPER) [Mao, Kim, Almenoff, Rudner, Kearney and Kindman (1996) Proc.Natl.Acad.Sci. U.S.A 93, 1993-1996], which we have identified for the first time in cardiac tissue.},
	article-doi = {10.1042/bj3220327},
	author = {Betto, R. and Teresi, A. and Turcato, F. and Salviati, G. and Sabbadini, R. A. and Krown, K. and Glembotski, C. C. and Kindman, L. A. and Dettbarn, C. and Pereon, Y. and Yasui, K. and Palade, P. T.},
	completed = {19970415},
	electronic-issn = {1470-8728},
	grantno = {HL42527/HL/NHLBI NIH HHS/United States},
	history = {1997/02/15 00:00 [entrez]},
	issue = {Pt 1},
	journal = {The Biochemical journal},
	keywords = {Animals, Calcium/metabolism, Calcium Channels/drug effects/*metabolism/physiology, Dogs, Dose-Response Relationship, Drug, Intracellular Membranes/drug effects/*metabolism, Microsomes/metabolism, Muscle Proteins/drug effects/*metabolism, Myocardium/*metabolism, Phosphorylcholine/*analogs \& derivatives/pharmacology, Ruthenium Red, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum/drug effects/*metabolism, Sphingosine/*analogs \& derivatives/pharmacology},
	language = {eng},
	linking-issn = {0264-6021},
	month = {Feb},
	nlm-unique-id = {2984726R},
	owner = {NLM},
	pages = {327--33},
	print-issn = {0264-6021},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20190501},
	source = {Biochem J. 1997 Feb 15;322 ( Pt 1)(Pt 1):327-33. doi: 10.1042/bj3220327.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Sphingosylphosphocholine modulates the ryanodine receptor/calcium-release channel of cardiac sarcoplasmic reticulum membranes.},
	title-abbreviation = {Biochem J},
	volume = {322 ( Pt 1)},
	year = {1997}
}

@article{Krown_1996_JClinInvest_98_2854,
	abstract = {In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFalpha induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFalpha stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFalpha-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFalpha. These findings suggest that the elevated TNFalpha levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFalpha-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.},
	article-doi = {10.1172/JCI119114},
	author = {Krown, K. A. and Page, M. T. and Nguyen, C. and Zechner, D. and Gutierrez, V. and Comstock, K. L. and Glembotski, C. C. and Quintana, P. J. and Sabbadini, R. A.},
	completed = {19970130},
	grantno = {HL-46345/HL/NHLBI NIH HHS/United States},
	history = {1996/12/15 00:00 [entrez]},
	issue = {12},
	journal = {The Journal of clinical investigation},
	keywords = {Analysis of Variance, Animals, Apoptosis/*drug effects, Benzoxazoles/metabolism, Cell Nucleus/metabolism, Cells, Cultured, Ceramides/pharmacology, DNA Damage/genetics, Electrophoresis, Agar Gel, Hydrogen Peroxide/pharmacology, Image Processing, Computer-Assisted, Microscopy, Fluorescence, Myocardial Ischemia/metabolism, Myocardium/*metabolism, Quinolinium Compounds/metabolism, Rats, Signal Transduction/physiology, Sphingolipids/metabolism/pharmacology, Sphingosine/metabolism/pharmacology, Tumor Necrosis Factor-alpha/*pharmacology},
	language = {eng},
	linking-issn = {0021-9738},
	month = {Dec},
	nlm-unique-id = {7802877},
	owner = {NLM},
	pages = {2854--65},
	print-issn = {0021-9738},
	publication-status = {ppublish},
	registry-number = {NGZ37HRE42 (Sphingosine)},
	revised = {20181113},
	source = {J Clin Invest. 1996 Dec 15;98(12):2854-65. doi: 10.1172/JCI119114.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death.},
	title-abbreviation = {J Clin Invest},
	volume = {98},
	year = {1996}
}

@article{Hanford_1996_MolEndocrinol_10_1719,
	abstract = {In cardiac myocytes, B-type natriuretic peptide (BNP) expression is induced with the rapid kinetics of a primary response gene. Like many other primary response gene transcripts, the BNP mRNA possesses destabilizing elements and is believed to be short-lived. The rapid induction of a short-lived transcript could be achieved partty by agonist-mediated increases in mRNA t1/2. Accordingly, the present study was undertaken to evaluate whether the alpha 1-adrenergic receptor agonist, phenylephrine (PE), a known inducer of BNP expression, could stabilize the BNP mRNA and, if so, what signaling pathways might be involved. In primary myocardial cells treated with a transcription inhibitor, the t1/2 of the BNP mRNA was found to be about 1 h in the absence of PE; however, in the presence of PE, the t1/2 increased to 5 h. It was shown that neither the calmodulin kinase inhibitor, KN-62, nor the protein tyrosine kinase inhibitor, tyrphostin, blocked PE-mediated stabilization of the BNP mRNA. However, either the protein kinase C (PKC) inhibitor, GF 109203X, or the mitogen-activated protein kinase kinase (MAPKK) inhibitor, PD 098059, effected some blockade of the stabilizing effects of PE. While maximal doses of PD 098059 nearly completely blocked PE-activated MAPK, stabilization was only partially inhibited. Moreover, maximal doses of GF 109203X, which only partially blocked PE-activated MAPK, nearly completely inhibited stabilization. Thus, while MAPK appears to be required for maximal agonist-mediated stabilization, PKC seems to play a dominant role, participating through both MAPK-dependent and -independent pathways. These results establish roles for both the PKC and MAPK families in alpha 1-adrenergic receptor-mediated stabilization of the BNP mRNA, suggesting that the rapid induction of BNP expression might be due, in part, to this agonist-mediated increase in mRNA t1/2.},
	address = {United States},
	article-doi = {10.1210/mend.10.12.8961280},
	author = {Hanford, D. S. and Glembotski, C. C.},
	completed = {19970320},
	grantno = {NS/HL-25073/NS/NINDS NIH HHS/United States},
	history = {1996/12/01 00:00 [entrez]},
	issue = {12},
	journal = {Molecular endocrinology (Baltimore, Md.)},
	keywords = {Adrenergic alpha-Agonists/pharmacology, Animals, Atrial Natriuretic Factor/drug effects/*genetics, Calcium-Calmodulin-Dependent Protein Kinases/antagonists \& inhibitors/*physiology, Cell Division/drug effects, Cells, Cultured, Colforsin/pharmacology, Dose-Response Relationship, Drug, Endothelin-1/pharmacology, Enzyme Inhibitors/pharmacology, Flavonoids/pharmacology, Half-Life, Heart/drug effects, Indoles/pharmacology, Maleimides/pharmacology, Myocardium/cytology/*metabolism, Natriuretic Peptide, Brain, Phenylephrine/pharmacology, Protein Kinase C/antagonists \& inhibitors/*physiology, Rats, Receptors, Adrenergic, alpha/drug effects/*metabolism, Signal Transduction},
	language = {eng},
	linking-issn = {0888-8809},
	month = {Dec},
	nlm-unique-id = {8801431},
	owner = {NLM},
	pages = {1719--27},
	print-issn = {0888-8809},
	publication-status = {ppublish},
	registry-number = {SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)},
	revised = {20180815},
	source = {Mol Endocrinol. 1996 Dec;10(12):1719-27. doi: 10.1210/mend.10.12.8961280.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: potential roles for protein kinase C and mitogen-activated protein kinase.},
	title-abbreviation = {Mol Endocrinol},
	volume = {10},
	year = {1996}
}

@article{Wollert_1996_JBiolChem_271_9535,
	abstract = {Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit beta (LIFRbeta) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRbeta in the hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and the LIFRbeta are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRbeta heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after alpha-adrenergic stimulation, both with regard to cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in cardiac cell size that is characterized by an increase in cell length but no significant change in cell width. Confocal laser microscopy of CT-1 stimulated cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after alpha-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and alpha-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to alpha-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5'-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gpl30/LIFRbeta-dependent signaling pathways.},
	address = {United States},
	article-doi = {10.1074/jbc.271.16.9535},
	article-pii = {S0021-9258(17)31370-4},
	author = {Wollert, K. C. and Taga, T. and Saito, M. and Narazaki, M. and Kishimoto, T. and Glembotski, C. C. and Vernallis, A. B. and Heath, J. K. and Pennica, D. and Wood, W. I. and Chien, K. R.},
	completed = {19960618},
	grantno = {etc.},
	history = {1996/04/19 00:00 [entrez]},
	issue = {16},
	journal = {The Journal of biological chemistry},
	keywords = {Actins/biosynthesis, Animals, Atrial Natriuretic Factor/biosynthesis, Cells, Cultured, Ciliary Neurotrophic Factor, Cytokines/biosynthesis/*pharmacology, Gene Expression/*drug effects, Genes, fos, Growth Inhibitors/*pharmacology, Heart/*drug effects, Humans, *Interleukin-6, Leukemia Inhibitory Factor, Leukemia Inhibitory Factor Receptor alpha Subunit, Lymphokines/*pharmacology, Mice, Myocardium/*cytology/metabolism/pathology, Nerve Growth Factors/pharmacology, Nerve Tissue Proteins/pharmacology, Proto-Oncogene Proteins c-fos/biosynthesis, Receptors, Cytokine/*physiology, Receptors, OSM-LIF, Recombinant Fusion Proteins/biosynthesis, Sarcomeres/drug effects/physiology/*ultrastructure, Signal Transduction, Transfection},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Apr},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {9535--45},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {AJ7U77BR8I (cardiotrophin 1)},
	revised = {20210210},
	source = {J Biol Chem. 1996 Apr 19;271(16):9535-45. doi: 10.1074/jbc.271.16.9535.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways.},
	title-abbreviation = {J Biol Chem},
	volume = {271},
	year = {1996}
}

@article{Post_1996_JBiolChem_271_8452,
	abstract = {In response to hormones and mechanical stretch, neonatal rat ventricular myocytes exhibit a hypertrophic response that is characterized by induction of cardiac-specific genes and increased myocardial cell size. Hypertrophic stimuli also activate mitogen-activated protein kinase (MAPK), an enzyme thought to play a central role in the regulation of cell growth and differentiation. To determine if MAPK activation is sufficient for acquisition of the molecular and morphological features of cardiac hypertrophy we compared four agonists that stimulate G protein-coupled receptors. Whereas phenylephrine and endothelin transactivate cardiac-specific promoter/luciferase reporter genes, increase atrial natriuretic factor (ANF) expression, and promote myofilament organization, neither carbachol nor ATP induces these responses. Interestingly, all four agonists activate both the p42 and the p44 isoforms of MAPK. Furthermore, the kinetics of MAPK activation are not different for the hypertrophic agonist phenylephrine and the nonhypertrophic agonist carbachol. Transient transfection of myocytes with dominant-interfering mutants of p42 and p44 MAPK failed to block phenylephrine-induced ANF expression, although Ras-induced gene expression was inhibited by expression of the mutant MAPK constructs. Moreover, PD 098059, an inhibitor of MAPK kinase, blocked phenylephrine-stimulated MAPK activity but not ANF reporter gene expression. Thus, MAPK activation is not sufficient for G protein receptor-mediated induction of cardiac cell growth and gene expression and is apparently not required for transcriptional activation of the ANF gene.},
	address = {United States},
	article-doi = {10.1074/jbc.271.14.8452},
	article-pii = {S0021-9258(17)45662-6},
	author = {Post, G. R. and Goldstein, D. and Thuerauf, D. J. and Glembotski, C. C. and Brown, J. H.},
	completed = {19960621},
	grantno = {NS 25037/NS/NINDS NIH HHS/United States},
	history = {1996/04/05 00:00 [entrez]},
	issue = {14},
	journal = {The Journal of biological chemistry},
	keywords = {Actin Cytoskeleton/ultrastructure, Adenosine Triphosphate/pharmacology, Adrenergic alpha-Agonists/pharmacology, Animals, Animals, Newborn, Atrial Natriuretic Factor/genetics, Calcium-Calmodulin-Dependent Protein Kinases/antagonists \& inhibitors/*metabolism, Carbachol/pharmacology, Cardiomegaly/*enzymology, Endothelins/pharmacology, Enzyme Activation, Flavonoids/pharmacology, Gene Expression/drug effects, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, *Mitogen-Activated Protein Kinases, Myocardium/cytology/*enzymology, Myosin-Light-Chain Kinase/genetics, Phenylephrine/pharmacology, Protein-Tyrosine Kinases/antagonists \& inhibitors/*metabolism, Proto-Oncogene Proteins p21(ras)/metabolism, Rats, Rats, Sprague-Dawley, Receptors, Cell Surface/physiology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Apr},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {8452--7},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)},
	revised = {20210210},
	source = {J Biol Chem. 1996 Apr 5;271(14):8452-7. doi: 10.1074/jbc.271.14.8452.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {271},
	year = {1996}
}

@article{Sprenkle_1995_CircRes_77_1060,
	abstract = {In the present study, cis elements in the 5'-flanking sequence (FS) of the rat atrial natriuretic factor (ANF) gene involved in regulating basal and alpha 1-adrenergic-inducible transcription were investigated. Truncation analyses using ANF-luciferase reporter constructs transfected into primary neonatal rat cardiac myocytes showed that an A/T-rich serum response element (SRE) at -114 bp of the ANF 5'-FS, which bound serum response factor (SRF), was required for basal and inducible transcription. In constructs composed of 134 bp of rat ANF 5'-FS driving luciferase (ANF-134Luc), mutations in the SRE at -114 bp disrupted SRF binding and ANF promoter activity. However, the same mutations in ANF-638Luc had little effect, suggesting a collaborating role for more distal sequences, such as the other SRE in ANF-638 at -406 bp. In ANF-638Luc, mutations in the SRE at -406 bp that disrupted SRF binding to that site decreased ANF reporter activity by only 25\%; however, mutating both of the SREs completely blocked alpha 1-adrenergic-inducible activity. Mutation analyses showed that an ... (SP-1)-like site at -69 bp, shown previously to confer inducibility in reporters with 134 bp of ANF 5'-FS, was not required in ANF-638Luc. However, double mutants in the SP-1-like region and either SRE completely blocked alpha 1-adrenergic-inducible ANF promoter activity. These findings emphasize that no single element is responsible for alpha 1-adrenergic agonist-regulated ANF transcription but that the SREs at -114 and -406 bp and the SP-1-like sequence at -69 bp mediate the effect in collaboration.},
	address = {United States},
	article-doi = {10.1161/01.res.77.6.1060},
	author = {Sprenkle, A. B. and Murray, S. F. and Glembotski, C. C.},
	completed = {19951226},
	grantno = {NS-25073/NS/NINDS NIH HHS/United States},
	history = {1995/12/01 00:00 [entrez]},
	issue = {6},
	journal = {Circulation research},
	keywords = {Adrenergic alpha-Agonists/*pharmacology, Animals, Atrial Natriuretic Factor/*genetics, Base Sequence, Cells, Cultured, *DNA-Binding Proteins/analysis, Electrophoresis, Molecular Sequence Data, Mutation, Myocardium/cytology/metabolism, *Nuclear Proteins/analysis/metabolism, Oligonucleotide Probes, Protein Binding, Rats, Serum Response Factor, *Transcription Factors/analysis, *Transcription, Genetic},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Dec},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {1060--9},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190706},
	source = {Circ Res. 1995 Dec;77(6):1060-9. doi: 10.1161/01.res.77.6.1060.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Involvement of multiple cis elements in basal- and alpha-adrenergic agonist-inducible atrial natriuretic factor transcription. Roles for serum response elements and an SP-1-like element.},
	title-abbreviation = {Circ Res},
	volume = {77},
	year = {1995}
}

@article{Krown_1995_FEBSLett_376_24,
	abstract = {Tumor necrosis factor-alpha (TNF alpha) is a potentially powerful anti-neoplastic agent; however, its therapeutic usefulness is limited by its cardiotoxic and negative inotropic effects. Accordingly, studies were undertaken to gain a better understanding of the mechanisms of TNF alpha-mediated cardiodepression. Single cell RT-PCR, [125I]TNF alpha ligand binding and Western immunoblotting experiments demonstrated that rat cardiac cells predominantly express type I TNF alpha receptors (TNFRI or p60). TNF alpha inhibited cardiac L-type Ca2+ channel current (ICa) and contractile Ca2+ transients. Thus, it is possible that the negative inotropic effects of TNF alpha are the result of TNFRI-mediated blockade of cardiac excitation-contraction coupling.},
	address = {England},
	article-doi = {10.1016/0014-5793(95)01238-5},
	article-pii = {0014-5793(95)01238-5},
	author = {Krown, K. A. and Yasui, K. and Brooker, M. J. and Dubin, A. E. and Nguyen, C. and Harris, G. L. and McDonough, P. M. and Glembotski, C. C. and Palade, P. T. and Sabbadini, R. A.},
	completed = {19960123},
	grantno = {HL42527/HL/NHLBI NIH HHS/United States},
	history = {1995/11/27 00:00 [entrez]},
	issue = {1-2},
	journal = {FEBS letters},
	keywords = {Animals, Base Sequence, Calcium/antagonists \& inhibitors/metabolism, Calcium Channels/metabolism, DNA Primers/chemistry, Fluorescent Dyes/metabolism, Gene Expression/genetics, Immunoblotting, In Vitro Techniques, Indoles/metabolism, Molecular Sequence Data, Myocardium/*metabolism, Patch-Clamp Techniques, Polymerase Chain Reaction, RNA, Messenger/analysis/metabolism, Rats, Rats, Sprague-Dawley, Receptors, Tumor Necrosis Factor/chemistry/genetics/*metabolism, Tumor Necrosis Factor-alpha/*pharmacology},
	language = {eng},
	linking-issn = {0014-5793},
	month = {Nov},
	nlm-unique-id = {0155157},
	owner = {NLM},
	pages = {24--30},
	print-issn = {0014-5793},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20190621},
	source = {FEBS Lett. 1995 Nov 27;376(1-2):24-30. doi: 10.1016/0014-5793(95)01238-5.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {TNF alpha receptor expression in rat cardiac myocytes: TNF alpha inhibition of L-type Ca2+ current and Ca2+ transients.},
	title-abbreviation = {FEBS Lett},
	volume = {376},
	year = {1995}
}

@article{McDonough_1994_CircRes_75_981,
	abstract = {The naturally occurring second messenger sphingosine (SPH) was examined for its ability to influence cardiac myocyte Ca2+ regulation. SPH inhibited intracellular Ca2+ transients in adult and neonatal rat ventricular myocytes. The inhibition was steeply dose dependent, with complete blockage of the Ca2+ transients occurring in the 20- to 25-mumol/L range. Whole-cell patch clamping revealed substantial inhibition of the L-type Ca2+ channel current (ICa) by SPH. The ability of SPH to block both the Ca2+ transients and ICa was not dependent on protein kinases, since the general protein kinase inhibitor H7 failed to prevent the actions of SPH. The specificity of the effect of SPH was determined in experiments showing that SPH analogues did not produce comparable effects. Neither the naturally occurring ceramide, N-stearoyl SPH, nor the cell-permeant ceramide, N-acetyl SPH, had SPH-like actions on the Ca2+ transients or L-type channel conductances. Caffeine-induced Ca2+ transients were also inhibited by the actions of SPH on cardiac sarcoplamic reticulum Ca2+ release, and the threshold for caffeine-induced Ca2+ release was raised. We conclude that SPH inhibits excitation-contraction coupling in cardiac myocytes by reducing the amount of entering "trigger Ca2+" for Ca(2+)-induced Ca2+ release and by simultaneously raising the threshold of the ryanodine receptor for Ca(2+)-induced Ca2+ release. Consequently, we propose that sphingolipids produced by the sphingomyelin signal transduction pathway could be physiologically relevant regulators of cardiac [Ca2+]i and therefore cardiac contractility.},
	address = {United States},
	article-doi = {10.1161/01.res.75.6.981},
	author = {McDonough, P. M. and Yasui, K. and Betto, R. and Salviati, G. and Glembotski, C. C. and Palade, P. T. and Sabbadini, R. A.},
	completed = {19941216},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1994/12/01 00:00 [entrez]},
	issue = {6},
	journal = {Circulation research},
	keywords = {Animals, Animals, Newborn, Calcium/*metabolism/physiology, Calcium Channels/*drug effects/metabolism/physiology, Ceramides/pharmacology, Heart/*drug effects/physiology, Muscle Proteins/metabolism, Myocardial Contraction, Myocardium/cytology/*metabolism, Rats, Rats, Sprague-Dawley, Ryanodine Receptor Calcium Release Channel, *Signal Transduction, Sphingosine/*pharmacology},
	language = {eng},
	linking-issn = {0009-7330},
	month = {Dec},
	nlm-unique-id = {0047103},
	owner = {NLM},
	pages = {981--9},
	print-issn = {0009-7330},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20190706},
	source = {Circ Res. 1994 Dec;75(6):981-9. doi: 10.1161/01.res.75.6.981.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Control of cardiac Ca2+ levels. Inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel conductance.},
	title-abbreviation = {Circ Res},
	volume = {75},
	year = {1994}
}

@article{Hanford_1994_JBiolChem_269_26227,
	abstract = {To better understand the molecular basis for increased atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) expression during overload-induced cardiac hypertrophy, we studied the induction of the genes in primary myocardial cells by the alpha 1-adrenergic agonist, phenylephrine (PE), a potent hypertrophic agent. PE augmented the transcription of both genes to similar extents, although the time course of mRNA accumulation differed. Increases in ANF mRNA were evident only after 6-8 h of PE exposure, when transcript levels were 2-4-fold over control. However, similar increases in BNP mRNA were observed as soon as 1 h of PE exposure. Moreover, while ANF mRNA levels continued to increase through 24 h of PE treatment, maximal levels of BNP mRNA (8-10-fold over control) were observed at 4 h, after which transcript levels declined to about 3-fold over control. The early induction of the BNP mRNA by PE was independent of protein synthesis, whereas the late induction of both genes required protein synthesis. Interestingly, the early BNP induction was only partially blocked by the transcription inhibitor, actinomycin D, indicating that, in part, the inductive effects of PE might be the result of transcript stabilization. Indeed, the BNP transcript, which was shown to possess a half-life of less than 1 h in control cells, was stabilized by the addition of PE, while the ANF transcript possessed a half-life of at least 24 h under all conditions. These data indicate that the induction of BNP by alpha 1-adrenergic agonists has characteristics of both a primary and secondary response gene, while ANF is a typical secondary response gene. Moreover, alpha 1-adrenergic stimulation enhances BNP expression through both transcriptional activation and transcript stabilization, while ANF expression is enhanced primarily transcriptionally.},
	address = {United States},
	article-pii = {S0021-9258(18)47183-9},
	author = {Hanford, D. S. and Thuerauf, D. J. and Murray, S. F. and Glembotski, C. C.},
	completed = {19941122},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1994/10/21 00:00 [entrez]},
	issue = {42},
	journal = {The Journal of biological chemistry},
	keywords = {*Adrenergic alpha-1 Receptor Agonists, Animals, Atrial Natriuretic Factor/biosynthesis/genetics, Cells, Cultured, Cycloheximide/pharmacology, Dactinomycin/pharmacology, Gene Expression Regulation/*drug effects, Myocardium/*metabolism, Natriuretic Peptide, Brain, Nerve Tissue Proteins/biosynthesis/*genetics, Phenylephrine/*pharmacology, RNA, Messenger/analysis/biosynthesis, Rats, Transcription, Genetic},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Oct},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {26227--33},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {98600C0908 (Cycloheximide)},
	revised = {20210212},
	source = {J Biol Chem. 1994 Oct 21;269(42):26227-33.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Brain natriuretic peptide is induced by alpha 1-adrenergic agonists as a primary response gene in cultured rat cardiac myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {269},
	year = {1994}
}

@article{Thuerauf_1994_JBiolChem_269_17772,
	abstract = {GATA-binding proteins are transcription factors that regulate the stage- and tissue-specific expression of globin genes in cells of the erythroid lineage. Recently, a cardiac GATA-binding protein was found to be the earliest gene expressed during cardiogenesis; however, the target genes of this transcription factor in the heart are unknown. Since brain natriuretic peptide (BNP) is activated early in cardiac growth and development, we evaluated whether it could serve as a target gene for GATA-binding protein-mediated induction. Upon isolating and sequencing 2.5 kilobases of the rat BNP 5'-flanking sequence (FS), a variety of putative transcriptional enhancer sites were identified, including several GATA consensus sequences (WGATAR), one of which apparently serves as the major promoter site. Primary myocardial cells were transfected with BNP/luciferase fusion genes; reporter expression was strongly induced by typical growth factors such as phorbol esters, serum, or alpha 1-adrenergic agonists, as well as by GATA-4 overexpression. Truncation analyses showed that inducibility mapped primarily to the proximal -116 base pair of the rat BNP 5'-FS, where there are two consensus GATA sites in addition to the GATA sequence at the TATA box. Point mutation analyses showed that at least one of the GATA sites was required to confer full GATA-4-inducible transcription. These results demonstrate that a proximal region of the rat BNP 5'-FS is required for growth factor- and GATA-inducible transcription, supporting the view that the BNP gene could serve as a target for GATA-binding proteins during early cardiac development.},
	address = {United States},
	article-pii = {S0021-9258(17)32374-8},
	author = {Thuerauf, D. J. and Hanford, D. S. and Glembotski, C. C.},
	completed = {19940808},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1994/07/08 00:00 [entrez]},
	issue = {27},
	journal = {The Journal of biological chemistry},
	keywords = {Amino Acid Sequence, Animals, Base Sequence, Brain/*metabolism, DNA, *Gene Expression Regulation, Molecular Sequence Data, Myocardium/*metabolism, Natriuretic Peptide, Brain, Nerve Tissue Proteins/*genetics/metabolism, Rats, Restriction Mapping, Transcription Factors/*metabolism, Transcription, Genetic},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jul},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {17772--5},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {9007-49-2 (DNA)},
	revised = {20210210},
	second-id = {GENBANK/U02972},
	source = {J Biol Chem. 1994 Jul 8;269(27):17772-5.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Regulation of rat brain natriuretic peptide transcription. A potential role for GATA-related transcription factors in myocardial cell gene expression.},
	title-abbreviation = {J Biol Chem},
	volume = {269},
	year = {1994}
}

@article{McDonough_1994_JBiolChem_269_9466,
	abstract = {To characterize the effects of the cellular events associated with contraction on atrial natriuretic factor (ANF) secretion, primary neonatal rat atrial myocytes were electrically paced to contract while being monitored for ANF release, cytoplasmic calcium, phosphoinositide hydrolysis, and protein kinase C activation. Similar measurements were also carried out in the presence of endothelin-1 (ET) for comparison of contraction-related and hormone-stimulated ANF secretion. Pacing (6-8 Hz) immediately increased ANF secretion by 3-5-fold and the time-averaged cytoplasmic calcium concentration (as monitored with indo-1 fluorescence) varied with pace frequency in a similar manner, suggesting that cytoplasmic calcium may play a key role in pace-induced ANF secretion. Furthermore, nifedipine and ryanodine, which inhibited the contractile calcium transients, inhibited pace-induced ANF release, whereas Bay K 8644 increased both the calcium transients and ANF secretion. Pace-induced ANF release was also completely inhibited by KN-62, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMK) but was not inhibited by chelerythrine, a protein kinase C-selective inhibitor. Pace-induced ANF release averaged 40\% of that elicited by ET which is known to require both PKC and CaMK for maximal effects on ANF secretion. The effects of pacing and ET on ANF secretion were approximately additive. In contrast to pacing, ET strongly stimulated phosphoinositide hydrolysis, activated PKC, and did not increase cytoplasmic calcium. Thus, regulation of ANF secretion by contraction rate depends primarily on the contractile calcium transients and CaMK and is independent of PKC.},
	address = {United States},
	article-pii = {S0021-9258(17)36904-1},
	author = {McDonough, P. M. and Stella, S. L. and Glembotski, C. C.},
	completed = {19940505},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1994/04/01 00:00 [entrez]},
	issue = {13},
	journal = {The Journal of biological chemistry},
	keywords = {*1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs \& derivatives, 3-Pyridinecarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology, Alkaloids, Analysis of Variance, Animals, Animals, Newborn, Atrial Natriuretic Factor/*metabolism, Benzophenanthridines, Calcium/*metabolism, Calcium-Calmodulin-Dependent Protein Kinases/antagonists \& inhibitors/*metabolism, Cells, Cultured, Cytoplasm/metabolism, Endothelins/*pharmacology, Fluorescent Dyes, Heart/drug effects/*physiology, Heart Atria, Indoles, Isoquinolines/pharmacology, Kinetics, Myocardial Contraction/drug effects/*physiology, Myocardium/enzymology/*metabolism, Phenanthridines/pharmacology, Phorbol 12, 13-Dibutyrate/pharmacology, Phosphatidylinositols/metabolism, Phosphoproteins/isolation \& purification/metabolism, Piperazines/pharmacology, Protein Kinase C/antagonists \& inhibitors/*metabolism, Rats, Rats, Sprague-Dawley, Spectrometry, Fluorescence},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Apr},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {9466--72},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210212},
	source = {J Biol Chem. 1994 Apr 1;269(13):9466-72.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Involvement of cytoplasmic calcium and protein kinases in the regulation of atrial natriuretic factor secretion by contraction rate and endothelin.},
	title-abbreviation = {J Biol Chem},
	volume = {269},
	year = {1994}
}

@article{Irons_1993_JBiolChem_268_23417,
	abstract = {Endothelin-1 (ET-1) is a potent stimulator of atrial natriuretic factor (ANF) secretion from myocardial cells. In heart tissue there are two ET receptor subtypes (ETA-R and ETB-R), which can be pharmacologically distinguished by the ET isopeptides ET-1 and ET-3. However, the identification of the ET-R subtype responsible for the rapid enhancement of ANF release, which occurs within minutes of exposing cardiac myocytes to ET, has not been investigated. In the present study ET-1 was about 100-fold more potent than ET-3 at stimulating membrane phosphoinositide hydrolysis, protein kinase C activation, and ANF release from purified primary atrial myocytes. These responses were completely abolished by BQ123, an ETA-R antagonist. Radioligand binding analyses showed that competitor peptides displaced 125I-ET-1 binding to atrial myocyte ET-Rs with a rank order of potency of ET-1 >> BQ123 > ET-3, a characteristic ETA-R pharmacological profile. While neither ET-1 or ET-3 altered forskolin-stimulated cAMP levels, suggesting the absence of the ETB-R, basal cAMP levels were also unaffected by the ETs. Northern analysis using ET-R subtype-specific probes demonstrated that the ETA-R transcript was present in the cultures at levels at least 50-fold greater than the ETB-R transcript. These findings demonstrate that the stimulation of the phosphatidylinositol/protein kinase C pathway, which is required for maximal ET-stimulated ANF release from primary atrial myocytes, is associated with the activation of only the ETA-R, thus defining a specific function for an endogenous ET-R in myocardial cells.},
	address = {United States},
	article-pii = {S0021-9258(19)49478-7},
	author = {Irons, C. E. and Murray, S. F. and Glembotski, C. C.},
	completed = {19931129},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1993/11/05 00:00 [entrez]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Atrial Natriuretic Factor/*metabolism, Base Sequence, Cells, Cultured, Colforsin/pharmacology, Cyclic AMP/metabolism, Endothelins/classification/*pharmacology, Enzyme Activation, Gene Expression, Heart Atria/*metabolism, In Vitro Techniques, Inositol Phosphates/metabolism, Molecular Sequence Data, Oligodeoxyribonucleotides/chemistry, Peptides, Cyclic/pharmacology, Protein Kinase C/*metabolism, RNA, Messenger/genetics, Rats, Receptors, Endothelin/*metabolism},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Nov},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {23417--21},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))},
	revised = {20210210},
	source = {J Biol Chem. 1993 Nov 5;268(31):23417-21.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Identification of the receptor subtype responsible for endothelin-mediated protein kinase C activation and atrial natriuretic factor secretion from atrial myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {268},
	year = {1993}
}

@article{Glembotski_1993_JBiolChem_268_20646,
	abstract = {The protease, alpha-thrombin (alpha Th), affects myocardial cell contractility, a feature common among agents that induce hypertrophy. However, it is not known whether cardiac myocytes possess alpha Th receptors (alpha Th-R), or if long term treatment with alpha Th can enhance growth and gene expression. In the present study primary neonatal rat ventricular myocytes expressed a 3.6-kilobase mRNA species that hybridized with a rat alpha Th-R-specific probe. After 48 h, alpha Th induced hypertrophy, sarcomeric organization, and enhanced atrial natriuretic factor (ANF) expression, all of which were blocked by the alpha Th-selective protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone. The alpha Th-R agonist peptide, SFLLRNPND, was a potent activator of ANF expression, however, the non-agonist, FLLRNPND, was inactive. Transfection experiments showed the enhancement of ANF expression by alpha Th to be transcriptional. The abilities of alpha Th to induce myocyte hypertrophy and to augment ANF transcription and peptide production were inhibited by the protein kinase C inhibitor, chelerythrine, and by the tyrosine kinase inhibitor, tyrphostin. Thus, myocardial cell alpha Th-Rs are stimulated by the specific proteolytic actions of alpha Th, and pathways involving both protein kinase C and protein tyrosine kinases are required for subsequent hypertrophy and ANF expression. Further, these findings suggest a new role for extracellular proteases as regulators of myocardial cell gene expression and growth.},
	address = {United States},
	article-pii = {S0021-9258(20)80773-X},
	author = {Glembotski, C. C. and Irons, C. E. and Krown, K. A. and Murray, S. F. and Sprenkle, A. B. and Sei, C. A.},
	completed = {19931020},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1993/09/25 00:00 [entrez]},
	issue = {27},
	journal = {The Journal of biological chemistry},
	keywords = {Alkaloids, Amino Acid Sequence, Animals, Animals, Newborn, Atrial Natriuretic Factor/analysis/*biosynthesis, Benzophenanthridines, Blotting, Northern, Cardiomegaly/chemically induced/*pathology, Catechols/pharmacology, Cells, Cultured, Gene Expression/*drug effects, Heart Ventricles, Kinetics, Molecular Sequence Data, Myocardium/*metabolism/pathology, Nitriles/pharmacology, Oligopeptides/chemical synthesis/*pharmacology, Phenanthridines/pharmacology, Platelet Aggregation Inhibitors/pharmacology, Polymerase Chain Reaction/methods, Protease Inhibitors/chemical synthesis/*pharmacology, Protein-Tyrosine Kinases/antagonists \& inhibitors, RNA, Messenger/analysis/*biosynthesis, Radioimmunoassay, Rats, Receptors, Cell Surface/drug effects/*physiology, Receptors, Thrombin, Thrombin/*pharmacology, *Tyrphostins},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Sep},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {20646--52},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.4.21.5 (Thrombin)},
	revised = {20210210},
	source = {J Biol Chem. 1993 Sep 25;268(27):20646-52.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Myocardial alpha-thrombin receptor activation induces hypertrophy and increases atrial natriuretic factor gene expression.},
	title-abbreviation = {J Biol Chem},
	volume = {268},
	year = {1993}
}

@article{McDonough_1993_AmJPhysiol_264_H625,
	abstract = {In ventricular myocytes, phenylephrine (PE) and endothelin (ET) stimulate phosphoinositide (PI) hydrolysis, cell growth, and expression of several genes [e.g., atrial natriuretic factor (ANF)] often associated with cardiac hypertrophy. In this study the production of inositol monophosphate (InsP) and diglyceride (DG), both products of PI hydrolysis, and ANF were monitored during long-term exposure (up to 72 h) to PE or ET. For PE, InsP production increased and continued unabated throughout the time course; DG levels also increased and remained elevated, and similar rates of ANF production were observed from 24 to 72 h. For ET, the initial InsP and DG responses equaled those to PE, but diminished by 24 h. ET-stimulated ANF production equaled the PE response at 24 h but subsided by 72 h. Adding PE to cells previously desensitized to ET elicited maximal InsP formation, indicating the desensitization was ET specific. These data emphasize that while phenylephrine and endothelin have similar initial effects on cardiac second messenger production and ANF expression, hormonally specific patterns develop over extended periods of exposure.},
	address = {United States},
	article-doi = {10.1152/ajpheart.1993.264.2.H625},
	author = {McDonough, P. M. and Brown, J. H. and Glembotski, C. C.},
	completed = {19930406},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1993/02/01 00:00 [entrez]},
	issue = {2 Pt 2},
	journal = {The American journal of physiology},
	keywords = {Animals, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Diglycerides/biosynthesis, Endothelins/*pharmacology, Hydrolysis, Inositol Phosphates/biosynthesis, Myocardium/*metabolism, Phenylephrine/*pharmacology, Phosphatidylinositols/*metabolism, Time Factors},
	language = {eng},
	linking-issn = {0002-9513},
	month = {Feb},
	nlm-unique-id = {0370511},
	owner = {NLM},
	pages = {H625--30},
	print-issn = {0002-9513},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20171213},
	source = {Am J Physiol. 1993 Feb;264(2 Pt 2):H625-30. doi: 10.1152/ajpheart.1993.264.2.H625.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Phenylephrine and endothelin differentially stimulate cardiac PI hydrolysis and ANF expression.},
	title-abbreviation = {Am J Physiol},
	volume = {264},
	year = {1993}
}

@article{Irons_1993_AmJPhysiol_264_H282,
	abstract = {We have investigated endothelin (ET)-regulated secretion of atrial natriuretic factor (ANF) from primary neonatal rat ventricular myocytes, where hormone release is thought to be constitutive. In a dose-dependent, nifedipine-sensitive manner, ET acutely enhanced ANF release by two- to fivefold over control cultures within 15 min of agonist exposure, demonstrating that ventricular myocytes display a primary characteristic of a regulated secretory cell type. Unlike atrial cultures, ET enhanced ANF release during the first 30 min of exposure; thereafter, secretion rates returned to control levels. KCl, however, effectively enhanced ANF release only during the first 15 min of exposure. Subcellular fractionation of ventricular culture homogenates did not reveal atrial-type dense secretory granules, and pulse-chase labeling experiments showed that the transit time of newly synthesized ANF was short in ventricular myocytes [time required for half of labeled ANF to be released from cells (t1/2) = 0.5-1.5 h) compared with atrial myocytes (t1/2 = 4 h). These results suggest that, whereas ventricular myocytes possess some of the characteristics of a constitutively secreting cell type (e.g., few, if any, dense secretory granules and rapid transit time for newly synthesized hormone); however, they also display the capacity for regulated secretion of ANF in response to the physiological agonist ET.},
	address = {United States},
	article-doi = {10.1152/ajpheart.1993.264.1.H282},
	author = {Irons, C. E. and Sei, C. A. and Glembotski, C. C.},
	completed = {19930305},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1993/01/01 00:00 [entrez]},
	issue = {1 Pt 2},
	journal = {The American journal of physiology},
	keywords = {Animals, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Cytoplasmic Granules/metabolism, Endothelins/pharmacology, Heart Ventricles, Myocardium/cytology/*metabolism, Nifedipine/pharmacology, Potassium Chloride/pharmacology, Precipitin Tests},
	language = {eng},
	linking-issn = {0002-9513},
	month = {Jan},
	nlm-unique-id = {0370511},
	owner = {NLM},
	pages = {H282--5},
	print-issn = {0002-9513},
	publication-status = {ppublish},
	registry-number = {I9ZF7L6G2L (Nifedipine)},
	revised = {20181130},
	source = {Am J Physiol. 1993 Jan;264(1 Pt 2):H282-5. doi: 10.1152/ajpheart.1993.264.1.H282.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Regulated secretion of atrial natriuretic factor from cultured ventricular myocytes.},
	title-abbreviation = {Am J Physiol},
	volume = {264},
	year = {1993}
}

@article{McDonough_1992_JBiolChem_267_11665,
	abstract = {While hormonal stimuli and mechanical stretch can induced cardiac-specific gene expression and in some cases cellular hypertrophy, the relationship between myocyte contraction frequency, gene expression, and myocyte growth has not been well characterized. In this study a new model system was developed in which cultures of neonatal rat ventricular myocytes were subjected to long term pacing of contractions with pulsatile electrical stimulation. Myocytes submitted to electrical stimulation for 3 days displayed dramatic increases in cellular size and myofibrillar organization, and a 5-10-fold increase in the expression of the cardiac genes atrial natriuretic factor and myosin light chain-2. Atrial natriuretic factor expression induced by electrical stimulation of contractions was inhibited by nifedipine or W7, indicating a dependence on calcium influx and calmodulin activity. Phosphoinositide hydrolysis and cAMP formation were not affected by electrical stimulation suggesting that gene induction occurred independently of the activation of protein kinases C or A above basal levels. These findings show that the cellular events associated with contraction, such as changes in cytoplasmic free calcium levels and/or cellular stretch, may serve as important determinants of myocyte growth and cardiac gene expression.},
	address = {United States},
	article-pii = {S0021-9258(19)49744-5},
	author = {McDonough, P. M. and Glembotski, C. C.},
	completed = {19920716},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1992/06/15 00:00 [entrez]},
	issue = {17},
	journal = {The Journal of biological chemistry},
	keywords = {3-Pyridinecarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology, Animals, Atrial Natriuretic Factor/biosynthesis/*genetics, Cells, Cultured, Electric Stimulation, Fluorescent Antibody Technique, *Gene Expression Regulation, Heart Ventricles/cytology/metabolism, *Myocardial Contraction/drug effects, Myocardium/cytology/*metabolism, Myosins/*genetics/metabolism, Nifedipine/pharmacology, RNA, Messenger/metabolism, Rats, Sulfonamides/pharmacology, Transcriptional Activation, Ventricular Function},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {11665--8},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {I9ZF7L6G2L (Nifedipine)},
	revised = {20210210},
	source = {J Biol Chem. 1992 Jun 15;267(17):11665-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Induction of atrial natriuretic factor and myosin light chain-2 gene expression in cultured ventricular myocytes by electrical stimulation of contraction.},
	title-abbreviation = {J Biol Chem},
	volume = {267},
	year = {1992}
}

@article{Lanson_1992_Circulation_85_1835,
	abstract = {BACKGROUND: Studies were carried out to characterize several biochemical features of cultured AT-1 cells. METHODS AND RESULTS: These cells were obtained from a transplantable atrial cardiomyocyte tumor lineage. Reverse transcriptase-polymerase chain reaction-based analyses demonstrated that the pattern of gene expression of cultured AT-1 cells was similar to that of adult atrial myocytes. AT-1 cells expressed atrial natriuretic factor (ANF), alpha-cardiac myosin heavy chain, alpha-cardiac actin, and connexin43. Radioimmunoassays verified that the cells synthesized, stored, and secreted ANF. Through size-exclusion, reversed-phase, and carboxymethyl-ion-exchange high-performance liquid chromatography, it was shown that cultured AT-1 cells stored ANF as pro-ANF (ANF-[1-126]), which was cosecretionally processed quantitatively to ANF-(1-98) and the bioactive 28-amino-acid ANF-(99-126). In addition, cultured AT-1 cells secreted ANF at almost a sixfold greater rate in response to endothelin-1, a potent secretagogue of ANF. KCl, metenkephalinamide, isoproterenol, phenylephrine, and 12-O-tetradecanoyl-phorbol-13-acetate also stimulated ANF release. CONCLUSIONS: These studies, in combination with previous findings, demonstrated that cultured AT-1 cells, while maintaining the ability to proliferate, have retained functional, biochemical, and ultrastructural features that are characteristic of adult atrial myocytes.},
	address = {United States},
	article-doi = {10.1161/01.cir.85.5.1835},
	author = {Lanson, N. A. Jr and Glembotski, C. C. and Steinhelper, M. E. and Field, L. J. and Claycomb, W. C.},
	completed = {19920601},
	grantno = {etc.},
	history = {1992/05/11 19:15 [entrez]},
	issue = {5},
	journal = {Circulation},
	keywords = {Animals, Atrial Natriuretic Factor/genetics/*metabolism, Chromatography, High Pressure Liquid, Connexins, Contractile Proteins/metabolism, *Gene Expression, Heart/*physiology, Isomerism, Membrane Proteins/genetics, Molecular Conformation, Myocardium/*metabolism/pathology, Polymerase Chain Reaction, Radioimmunoassay, Tumor Cells, Cultured},
	language = {eng},
	linking-issn = {0009-7322},
	month = {May},
	nlm-unique-id = {0147763},
	owner = {NLM},
	pages = {1835--41},
	print-issn = {0009-7322},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190623},
	source = {Circulation. 1992 May;85(5):1835-41. doi: 10.1161/01.cir.85.5.1835.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Gene expression and atrial natriuretic factor processing and secretion in cultured AT-1 cardiac myocytes.},
	title-abbreviation = {Circulation},
	volume = {85},
	year = {1992}
}

@article{Irons_1992_JBiolChem_267_5211,
	abstract = {Endothelin (ET), a potent stimulator of atrial natriuretic factor (ANF) secretion in atrial myocyte cultures, has been hypothesized to act via the stimulation of protein kinase C (PKC). This study was carried out in order to determine if ET activates PKC in atrial cultures and whether this activation fully accounts for the effects of ET on ANF secretion. By monitoring the phosphorylation of p80 upon exposure to phorbol ester or ET, it was shown that ET activated PKC in atrial cultures, but to a lesser extent than phorbol ester. In contrast, ET stimulated ANF secretion to a level five times greater than phorbol ester, indicating that PKC activation alone does not fully account for the effects of ET on ANF secretion. Down-regulation of PKC or exposure to the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) resulted in a 50\% decrease in ET-stimulated ANF secretion. Interestingly, increasing calcium influx with BAY K 8644 stimulated ANF secretion but did not effect the phosphorylation of p80, indicating a PKC-independent pathway of ANF secretion. Similarly, a component of ET-stimulated secretion that required calcium influx was independent of PKC activation but was sensitive to the Ca2+/calmodulin kinase (CaMK) inhibitor KN-62. Complete inhibition of ET-mediated ANF secretion was obtained only in the presence of both H7 and KN-62. These results demonstrate that ET activates PKC in atrial myocyte cultures and that the full effects of ET on ANF secretion require both PKC and Ca2+/calmodulin kinase activities.},
	address = {United States},
	article-pii = {S0021-9258(18)42753-6},
	author = {Irons, C. E. and Sei, C. A. and Hidaka, H. and Glembotski, C. C.},
	completed = {19920414},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1992/03/15 00:00 [entrez]},
	issue = {8},
	journal = {The Journal of biological chemistry},
	keywords = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, 3-Pyridinecarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology, Animals, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Endothelins/*pharmacology, Heart/drug effects/*physiology, Heart Atria, Isoquinolines/pharmacology, Kinetics, Myocardium/enzymology, Nifedipine/pharmacology, Phorbol 12, 13-Dibutyrate/pharmacology, Phosphorylation, Piperazines/pharmacology, Protein Kinase C/antagonists \& inhibitors/*metabolism, Protein Kinase Inhibitors, Protein Kinases/*metabolism, Rats, *Sulfonamides},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Mar},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {5211--6},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {I9ZF7L6G2L (Nifedipine)},
	revised = {20210210},
	source = {J Biol Chem. 1992 Mar 15;267(8):5211-6.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Protein kinase C and calmodulin kinase are required for endothelin-stimulated atrial natriuretic factor secretion from primary atrial myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {267},
	year = {1992}
}

@article{Sei_1992_MolEndocrinol_6_309,
	abstract = {Cardiac myocytes store the 126-amino acid precursor of atrial natriuretic factor (pro-ANF), yet the mature, bioactive 28-amino acid peptide, ANF-(99-126), and the resulting N-terminal product, ANF-(1-98), are the forms of the hormone that are released by the heart and found in the circulation. Although previous studies have shown that the maturation of ANF takes place in the heart, it is not known whether it occurs in or on the myocyte concurrently with secretion, or whether cleavage takes place postsecretionally on either the myocyte surface or the surface of a nonmuscle cardiac cell. To address these questions, experiments were carried out in the present study using primary atrial cultures that had been prepared such that greater than 90\% of the cells were myocytes. Reversed-phase and ion-exchange HPLC, coupled with immunoprecipitation of biosynthetically labeled ANF, showed that the stored peptide, pro-ANF, was cleaved between residues 98 and 99 such that ANF-(1-98) and (99-126) accumulated in the medium. Coupling biosynthetic labeling with timed secretion experiments showed that the extent of ANF processing was not dependent on the time after secretion; maximal levels of processing were observed at all secretion times examined. Additionally, the processing-competent myocyte-enriched cultures were unable to cleave exogenously added pro-ANF. These results indicate that the myocyte is the cell type responsible for pro-ANF maturation and that this cleavage event takes place cosecretionally.},
	address = {United States},
	article-doi = {10.1210/mend.6.3.1533896},
	author = {Sei, C. A. and Hand, G. L. and Murray, S. F. and Glembotski, C. C.},
	completed = {19920618},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1992/03/01 00:00 [entrez]},
	issue = {3},
	journal = {Molecular endocrinology (Baltimore, Md.)},
	keywords = {Animals, Atrial Natriuretic Factor/*biosynthesis/*metabolism, Cells, Cultured, Immunohistochemistry, Kinetics, Myocardium/cytology/*metabolism, Protein Precursors/*metabolism, Protein Processing, Post-Translational, Rats},
	language = {eng},
	linking-issn = {0888-8809},
	month = {Mar},
	nlm-unique-id = {8801431},
	owner = {NLM},
	pages = {309--19},
	print-issn = {0888-8809},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20181130},
	source = {Mol Endocrinol. 1992 Mar;6(3):309-19. doi: 10.1210/mend.6.3.1533896.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The cosecretional maturation of atrial natriuretic factor by primary atrial myocytes.},
	title-abbreviation = {Mol Endocrinol},
	volume = {6},
	year = {1992}
}

@article{Glembotski_1991_CanJPhysiolPharmacol_69_1525,
	abstract = {In contrast to most other endocrine peptides ANF is stored in the heart as part of a larger prohormone, often called pro-ANF, yet is found in the circulation as a 28 amino acid peptide, called ANF. It has been shown that the conversion of the 126 amino acid pro-ANF to ANF occurs in the heart. This paper summarizes studies from our laboratory that have used a primary neonatal rat heart cell culture system to investigate the location and mechanism of this relatively unusual processing event. We have found that in culture the maintenance of the cells in a glucocorticoid-containing serum-free medium is required to observe processing as occurs in vivo. The cells contain the prohormone while ANF accumulates in the medium. Various experiments with protease inhibitors, pulse-chase biosynthetic labeling, incubation of cells with ANF-related peptides, and enrichment of cultures for myocytes have resulted in our conclusion that the processing of pro-ANF takes place most likely within the cardiac myocyte just prior to, but in concert with secretion. We have expanded on the use of this processing-competent atrial myocyte culture system to investigate mechanisms of stimulated ANF secretion. It has been shown that the activation of several phospholipase C-coupled receptors (e.g., alpha 1-adrenergic and endothelin receptors) produces a robust release of ANF, but only in cultures that have been maintained under appropriate conditions. Further, it is apparent that the phenylephrine- or endothelin-mediated release of ANF depends in part on influx of extracellular calcium (Ca2+o), while the remaining component of stimulated release may depend on mobilization of intracellular calcium. It also appears that these agonists produce an initial phase of stimulated release, occurring within the first 5 min of agonist exposure, independent of Ca2+o, and a sustained phase that persists as long as the agonists remain on the cells, and depends on the presence of Ca2+o and thus calcium influx. Taken together our studies indicate that the hormonal environment may be an important factor directing the development of differentiated endocrine functions by atrial myocytes and may be involved in the regulation of ANF expression, biosynthesis, and secretion.},
	address = {Canada},
	article-doi = {10.1139/y91-228},
	author = {Glembotski, C. C. and Irons, C. E. and Sprenkle, A. B. and Sei, C. A.},
	completed = {19920310},
	grantno = {NS25037/NS/NINDS NIH HHS/United States},
	history = {1991/10/01 00:00 [entrez]},
	issue = {10},
	journal = {Canadian journal of physiology and pharmacology},
	keywords = {Animals, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Humans, Myocardium/*metabolism},
	language = {eng},
	linking-issn = {0008-4212},
	month = {Oct},
	nlm-unique-id = {0372712},
	owner = {NLM},
	pages = {1525--36},
	print-issn = {0008-4212},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190720},
	source = {Can J Physiol Pharmacol. 1991 Oct;69(10):1525-36. doi: 10.1139/y91-228.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Studies of ANF processing and secretion using a primary cardiocyte culture model.},
	title-abbreviation = {Can J Physiol Pharmacol},
	volume = {69},
	year = {1991}
}

@article{Sei_1991_JBiolChem_266_15910,
	abstract = {It has been shown recently that alpha-adrenergic agonists can stimulate atrial natriuretic factor (ANF) expression in ventricular cardiac myocytes; however, little is known about the intracellular signals mediating this activation. The present study focused on the potential roles of calcium-regulated kinases and calcium influx in the alpha-adrenergic stimulation of ANF gene expression in ventricular myocardial cell cultures. Myocardial cells maintained for 48 h in serum-free medium supplemented with phenylephrine (PE) possessed up to 15-fold higher levels of ANF peptide and ANF mRNA than control cells. The removal of PE, or the addition of nifedipine, resulted in a rapid decline in ANF expression, suggesting that the sustained elevation of some intracellular messenger (e.g. calcium and/or phospholipid hydrolysis products) was required for the adrenergic response. The calcium channel agonist BAY K 8644 was capable of increasing ANF expression in a nifedipine-sensitive manner; however, unlike PE, it did not stimulate phosphoinositide hydrolysis. The protein kinase C inhibitor, H7, caused an approximate 75\% reduction in PE-stimulated ANF expression, but had no effect on BAY K-stimulated expression. W7, a calcium/calmodulin inhibitor, completely blocked the effects of both PE and BAY K 8644. The addition of either H7 or W7 24 h after the PE addition resulted in a decline of ANF expression. These results indicate that alpha-adrenergic agonists augment ANF gene expression through at least two pathways, one that is H7-sensitive, perhaps involving the sustained activation of protein kinase C, and the other that is W7-sensitive, perhaps involving the sustained activation of calmodulin-regulated kinases. Further, it appears that BAY K 8644-mediated increases in ANF expression are independent of protein kinase C activation and dependent on calmodulin-regulated events.},
	address = {United States},
	article-pii = {S0021-9258(18)98495-4},
	author = {Sei, C. A. and Irons, C. E. and Sprenkle, A. B. and McDonough, P. M. and Brown, J. H. and Glembotski, C. C.},
	completed = {19910926},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1991/08/25 00:00 [entrez]},
	issue = {24},
	journal = {The Journal of biological chemistry},
	keywords = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, 3-Pyridinecarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology, Adrenergic alpha-Agonists/*pharmacology, Animals, Atrial Natriuretic Factor/*genetics, Calcium/*metabolism, Calmodulin/*metabolism, Cells, Cultured, Gene Expression, Heart/drug effects, Hydrolysis, Isoquinolines/pharmacology, Myocardium/enzymology/*metabolism, Nifedipine/pharmacology, Phenylephrine/pharmacology, Phosphatidylinositols/metabolism, Piperazines/pharmacology, Protein Kinase C/antagonists \& inhibitors/*metabolism, Rats, Sulfonamides/pharmacology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Aug},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {15910--6},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210210},
	source = {J Biol Chem. 1991 Aug 25;266(24):15910-6.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The alpha-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways.},
	title-abbreviation = {J Biol Chem},
	volume = {266},
	year = {1991}
}

@article{Knowlton_1991_JBiolChem_266_7759,
	abstract = {To study the mechanisms which mediate the transcriptional activation of cardiac genes during alpha adrenergic stimulation, the present study examined the regulated expression of three cardiac genes, a ventricular embryonic gene (atrial natriuretic factor, ANF), a constitutively expressed contractile protein gene (cardiac MLC-2), and a cardiac sodium channel gene. alpha 1-Adrenergic stimulation activates the expression and release of ANF from neonatal ventricular cells. As assessed by RNase protection analyses, treatment with alpha-adrenergic agonists increases the steady-state levels of ANF mRNA by greater than 15-fold. However, a rat cardiac sodium channel gene mRNA is not induced, indicating that alpha-adrenergic stimulation does not lead to an increase in the expression of all cardiac genes. Studies employing a series of rat ANF luciferase and rat MLC-2 luciferase fusion genes identify 315- and 92-base pair cis regulatory sequences within an embryonic gene (ANF) and a constitutively expressed contractile protein gene (MLC-2), respectively, which mediate alpha-adrenergic-inducible gene expression. Transfection of various ANF luciferase reporters into neonatal rat ventricular cells demonstrated that upstream sequences which mediate tissue-specific expression (-3003 to -638) can be segregated from those responsible for inducibility. The lack of inducibility of a cardiac Na+ channel gene, and the segregation of ANF gene sequences which mediate cardiac specific from those which mediate inducible expression, provides further insight into the relationship between muscle-specific and inducible expression during cardiac myocyte hypertrophy. Based on these results, a testable model is proposed for the induction of embryonic cardiac genes and constitutively expressed contractile protein genes and the noninducibility of a subset of cardiac genes during alpha-adrenergic stimulation of neonatal rat ventricular cells.},
	address = {United States},
	article-pii = {S0021-9258(20)89515-5},
	author = {Knowlton, K. U. and Baracchini, E. and Ross, R. S. and Harris, A. N. and Henderson, S. A. and Evans, S. M. and Glembotski, C. C. and Chien, K. R.},
	completed = {19910529},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1991/04/25 00:00 [entrez]},
	issue = {12},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Atrial Natriuretic Factor/*genetics, Base Sequence, Chimera, Embryo, Mammalian, Fluorescent Antibody Technique, Gene Expression Regulation, Heart Ventricles/cytology/*drug effects, Luciferases/genetics, Molecular Sequence Data, Myocardium/*chemistry, Myosins/*genetics, Norepinephrine/pharmacology, RNA, Messenger/analysis/biosynthesis, Rats, Rats, Inbred Strains, Receptors, Adrenergic, alpha/*drug effects, Regulatory Sequences, Nucleic Acid, Sodium Channels/chemistry/genetics, Transfection},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Apr},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7759--68},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {X4W3ENH1CV (Norepinephrine)},
	revised = {20210219},
	source = {J Biol Chem. 1991 Apr 25;266(12):7759-68.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression.},
	title-abbreviation = {J Biol Chem},
	volume = {266},
	year = {1991}
}

@article{Shubeita_1990_JBiolChem_265_20555,
	abstract = {The present study examined the effects of endothelin-1 on phosphoinositide hydrolysis, diacylglycerol formation, and the induction of myocardial cell hypertrophy utilizing a well characterized cultured neonatal rat myocardial cell model. In this system, a hypertrophic response can be assessed by increases in myocardial cell size, an increase in the assembly of an individual contractile protein (myosin light chain-2) into organized contractile units, accumulation of contractile proteins, the activation of a program of immediate early gene expression, and the induction of genes encoding contractile and embryonic proteins (Iwaki, K., Sukhatme, V., Shubeita, H.E., Chien, K.R., (1990) J. Biol. Chem. 265, 13809-13817). Utilizing these criteria, the present study documents that stimulation with endothelin-1 can produce myocardial cell hypertrophy, induce the expression and release of ANF in ventricular cells, and can activate the transcription of cardiac-specific genes. In addition, endothelin-1 stimulates phosphoinositide hydrolysis and the accumulation of diacylglycerol. It is proposed that endothelin-1 stimulation may represent an important paracrine mechanism for the in vivo regulation of cardiac growth and hypertrophy.},
	address = {United States},
	article-pii = {S0021-9258(17)30538-0},
	author = {Shubeita, H. E. and McDonough, P. M. and Harris, A. N. and Knowlton, K. U. and Glembotski, C. C. and Brown, J. H. and Chien, K. R.},
	completed = {19901228},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1990/11/25 00:00 [entrez]},
	issue = {33},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Animals, Newborn, Cells, Cultured, Diglycerides/metabolism, Endothelins/*pharmacology, Gene Expression/*drug effects, Heart Ventricles/drug effects/metabolism/ultrastructure, Kinetics, Myocardium/*metabolism, Myosins/genetics, Phosphatidylinositols/*metabolism, Plasmids, Rats, Rats, Inbred Strains, Sarcomeres/drug effects/*ultrastructure},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Nov},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {20555--62},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.6.4.1 (Myosins)},
	revised = {20210210},
	source = {J Biol Chem. 1990 Nov 25;265(33):20555-62.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy.},
	title-abbreviation = {J Biol Chem},
	volume = {265},
	year = {1990}
}

@article{Shields_1990_JBiolChem_265_10905,
	abstract = {Atrial natriuretic factor (ANF) is stored within atrial myocyte secretory granules as pro-ANF (ANF-(1-126] and is proteolytically processed co-secretionally C-terminal to a single basic amino acid to form ANF-(1-98) and the bioactive product ANF-(99-126). Pro-ANF is also expressed in certain non-cardiac neuroendocrine cell types (e.g. brain, adrenal). Although the relatively low levels of the peptide in these cell types have precluded detailed processing and secretion studies using cultured cells, some work with tissue extracts suggests that pro-ANF is pre-secretionally processed between or C-terminal to Arg101-Arg102 in such cells. In order to assess whether cultured non-cardiac endocrine cells process pro-ANF pre- or co-secretionally, and to establish whether both paired and single basic amino acids can serve as cleavage sites, transfection studies were carried out using the adrenocorticotropic hormone (ACTH)-producing pituitary tumor cell line AtT-20/D-16v. These cells normally cleave pro-ACTH/endorphin pre-secretionally at selected, but not all, pairs of basic amino acids to a variety of product peptides. A prepro-ANF expression plasmid was constructed and transfected into the AtT-20 cells. The resulting ANF/AtT-20 cell clone selected for this study expressed ACTH at levels similar to the untransfected wild type cells and secreted immunoreactive ANF-related material at a rate of approximately 1 fmol/min/10(5) cells, which was about 10\% the rate of ACTH secretion. The rates of secretion of both ANF and ACTH could be increased 3-5-fold with a variety of known AtT-20 cell secretagogues including phorbol esters and the beta-adrenergic agonist, isoproterenol, thus indicating that both peptides were routed through regulated secretory pathways. Utilizing a combination of specific antisera directed against various regions of pro-ANF, size exclusion and reversed phase high performance liquid chromatography, and peptide mapping, it was shown that the ANF/AtT-20 cells contained and secreted the bioactive peptide ANF-(103-126) and -(1-97). These results indicate that the ANF/AtT-20 cells specifically cleave pro-ANF pre-secretionally at the same single basic site used by cardiac tissue; this single basic cleavage is apparently followed by removal of Arg98 by carboxypeptidase H. It is also apparent that the cells can cleave at the sole paired basic site in pro-ANF, which is the probable cleavage site used by neurons and some other endocrine cells that express low levels of the prohormone.(ABSTRACT TRUNCATED AT 400 WORDS)},
	address = {United States},
	article-pii = {S0021-9258(19)38532-1},
	author = {Shields, P. P. and Sprenkle, A. B. and Taylor, E. W. and Glembotski, C. C.},
	completed = {19900801},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1990/07/05 00:00 [entrez]},
	issue = {19},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/*biosynthesis/metabolism, Amino Acid Sequence, Animals, Atrial Natriuretic Factor/*genetics/metabolism, Cadmium/pharmacology, Cadmium Chloride, Carboxypeptidase H, Carboxypeptidases/metabolism, Chromatography, High Pressure Liquid, *Gene Expression, Isoproterenol/pharmacology, Mice, Molecular Sequence Data, Molecular Weight, Peptide Fragments/metabolism, Peptide Mapping, Pituitary Neoplasms/*metabolism, Plasmids, Protein Precursors/*genetics, *Protein Processing, Post-Translational, Rats, Tetradecanoylphorbol Acetate/pharmacology, Transfection, Tumor Cells, Cultured},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jul},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {10905--11},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {NI40JAQ945 (Tetradecanoylphorbol Acetate)},
	revised = {20210210},
	source = {J Biol Chem. 1990 Jul 5;265(19):10905-11.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Rat pro-atrial natriuretic factor expression and post-translational processing in mouse corticotropic pituitary tumor cells.},
	title-abbreviation = {J Biol Chem},
	volume = {265},
	year = {1990}
}

@article{Sei_1990_JBiolChem_265_7166,
	abstract = {Since calcium is involved in both excitation-secretion and excitation-contraction coupling, it was of interest to evaluate its involvement in atrial natriuretic factor (ANF) release from atrial cardiocytes. In medium containing physiological levels of calcium (1.4 mM), the secretion of ANF from primary atrial cells was stimulated from 3- to 6-fold by a variety of agents including KCl, phenylephrine, and endothelium (ET). However, in medium containing 2 nM calcium, KCl was incapable of increasing ANF secretion above basal levels, while the stimulatory effects of phenylephrine and ET were only partially diminished. Nifedipine or verapamil could mimic the effects of the 2 nM calcium medium on KCl-, phenylephrine-, and ET-stimulated ANF secretion. Kinetic studies indicated that during the initial 5 min of ET-stimulated secretion the cells exhibited little requirement for extracellular calcium; however, the requirement was more apparent during the sustained secretion observed between 10 min and 2 h of secretagogue exposure. Additionally, the stimulation of ANF secretion by ET increased to a maximum of about 15-fold over basal by 10-min after ET application; subsequent to this time there was an apparent functional desensitization wherein the rate of secretion decreased by approximately 3-4-fold and remained at this level for the duration of secretagogue exposure up to 2 h. All forms of stimulated secretion could be inhibited through ionomycin-mediated depletion of intracellular calcium pools. Taken together, these results indicate that atrial cardiocytes require both extracellular and intracellular calcium to support maximal rates of stimulated ANF secretion, and that intracellular calcium pools may be used during the early phase of secretion, while the extracellular source of calcium may be important for the sustained phase of secretion.},
	address = {United States},
	article-pii = {S0021-9258(19)39094-5},
	author = {Sei, C. A. and Glembotski, C. C.},
	completed = {19900604},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1990/05/05 00:00 [entrez]},
	issue = {13},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/metabolism, Animals, Animals, Newborn, Atrial Function, Atrial Natriuretic Factor/*metabolism, Calcium/*pharmacology, Cells, Cultured, Egtazic Acid/pharmacology, Endothelins, Endothelium, Vascular/physiology, Heart/*physiology, Heart Atria/drug effects, Kinetics, Nifedipine/pharmacology, Peptides/*pharmacology, Phenylephrine/*pharmacology, Pituitary Neoplasms/metabolism, Potassium Chloride/*pharmacology, Rats, Rats, Inbred Strains},
	language = {eng},
	linking-issn = {0021-9258},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7166--72},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {SY7Q814VUP (Calcium)},
	revised = {20210210},
	source = {J Biol Chem. 1990 May 5;265(13):7166-72.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Calcium dependence of phenylephrine-, endothelin-, and potassium chloride-stimulated atrial natriuretic factor secretion from long term primary neonatal rat atrial cardiocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {265},
	year = {1990}
}

@article{Stone_1990_CurrEyeRes_9_287,
	abstract = {Acid extracts of guinea pig and rhesus monkey anterior uvea, choroid and retina contain immunoreactive VIP. By reversed phase high performance liquid chromatography, the immunoreactive material from these ocular tissues elutes at a position similar to synthetic porcine VIP. Only in the guinea pig anterior uvea is a second smaller peak detected. By size exclusion high performance liquid chromatography, the peptide in the monkey anterior uvea, choroid and retina elutes in the identical position as the synthetic porcine VIP standard with an apparent molecular weight of 3450 daltons. We conclude that a single form of VIP, chromatographically similar to the porcine standard, is the predominant form of the peptide in the eye of guinea pig and rhesus monkey.},
	address = {England},
	article-doi = {10.3109/02713689009044525},
	author = {Stone, R. A. and Wilson, C. M. and Glembotski, C. C.},
	completed = {19900711},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1990/03/01 00:00 [entrez]},
	issue = {3},
	journal = {Current eye research},
	keywords = {Animals, Choroid/analysis, Chromatography, High Pressure Liquid, Eye/*analysis, Guinea Pigs, Macaca mulatta, Rabbits, Radioimmunoassay, Retina/analysis, Swine, Uvea/analysis, Vasoactive Intestinal Peptide/*analysis/metabolism},
	language = {eng},
	linking-issn = {0271-3683},
	month = {Mar},
	nlm-unique-id = {8104312},
	owner = {NLM},
	pages = {287--91},
	print-issn = {0271-3683},
	publication-status = {ppublish},
	registry-number = {37221-79-7 (Vasoactive Intestinal Peptide)},
	revised = {20190828},
	source = {Curr Eye Res. 1990 Mar;9(3):287-91. doi: 10.3109/02713689009044525.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Chromatographic characterization of vasoactive intestinal polypeptide in guinea pig and rhesus monkey eyes.},
	title-abbreviation = {Curr Eye Res},
	volume = {9},
	year = {1990}
}

@article{Shields_1989_JBiolChem_264_9322,
	abstract = {Atrial natriuretic factor (ANF) is stored in atrial myocytes as a prohormone (ANF-(1-126] and is cosecretionally processed to the circulating ANF-related peptides, ANF-(1-98) and ANF-(99-126). Recently, we have shown that the cosecretional processing of ANF can be replicated in primary cultures of neonatal rat atrial myocytes maintained under serum-free conditions and that glucocorticoids are responsible for supporting this processing activity. Activators of protein kinase C (phorbol esters and alpha-adrenergic agonists) and of protein kinase A (cAMP analogs, forskolin, and beta-adrenergic agonists) were tested for their abilities to alter the rate of ANF secretion from the primary cultures. ANF secretion was stimulated approximately 4-fold after a 1-h incubation of the cultures with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA); maximal release occurred at about 100 nM TPA. Reversed-phase high performance liquid chromatography analysis of secreted material indicated that the cells efficiently cosecretionally processed ANF under both basal and TPA-stimulated conditions. However, incubating the cultures for more than 1 h with TPA resulted in a blunted secretory response to further TPA challenge and a 40-50\% decrease in the quantity of ANF in the cells. The alpha-adrenergic receptor agonist phenylephrine was also capable of stimulating ANF secretion by about 4-fold at a half-maximal dose of about 1 microM. Phenylephrine-stimulated ANF secretion was inhibited by the alpha 1-adrenergic antagonist prazosin with half-maximal inhibition occurring at approximately 1 nM. Forskolin, 8-bromoadenosine 3':5'-cyclic monophosphate, and N6-2(1)-O-dibutyryladenosine 3':5'-cyclic monophosphate inhibited basal, TPA- and phenylephrine-stimulated ANF secretion. The beta-adrenergic agonist isoproterenol partially inhibited phenylephrine-stimulated ANF secretion with the maximal effect occurring at 1 nM. These results indicate that ANF secretion from the neonatal rat atrial cultures is enhanced by activators of protein kinase C, and decreased by activators of protein kinase A, and that these secretory effects may be mediated through the actions of alpha- and beta-adrenergic receptors, respectively.},
	address = {United States},
	article-pii = {S0021-9258(18)60534-4},
	author = {Shields, P. P. and Glembotski, C. C.},
	completed = {19890705},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1989/06/05 00:00 [entrez]},
	issue = {16},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Animals, Newborn/*physiology, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Enzyme Activation/drug effects, Heart Atria/enzymology/*metabolism, Peptide Fragments/*metabolism, Phenylephrine/pharmacology, Prazosin/pharmacology, Protein Kinase C/*metabolism, Protein Kinases/*metabolism, Rats, Rats, Inbred Strains, Receptors, Adrenergic, alpha/drug effects, Tetradecanoylphorbol Acetate/pharmacology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {9322--8},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {XM03YJ541D (Prazosin)},
	revised = {20210212},
	source = {J Biol Chem. 1989 Jun 5;264(16):9322-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Regulation of atrial natriuretic factor-(99-126) secretion from neonatal rat primary atrial cultures by activators of protein kinases A and C.},
	title-abbreviation = {J Biol Chem},
	volume = {264},
	year = {1989}
}

@article{Glembotski_1989_CellMolNeurobiol_9_57,
	abstract = {1. Aim. The biochemical characteristics of atrial natriuretic peptide receptors (ANP-R) derived from rat vascular smooth muscle (A-10 cell line) and central nervous system (CNS; olfactory bulb) tissue were compared. 2. Method and Results. ANP-Rs from each source were solubilized with 40 to 65\% efficiency utilizing the nonionic detergent Lubrol-PX. Upon solubilization, the ANP-R from each source maintained the ability to bind 125I-ANP (99-126) with a high affinity; Scatchard analysis indicated that the VSMC ANP-R displayed a Kd for the radioligand of approximately 10 pM, whereas the olfactory receptor possessed a Kd of about 165 pM. The Bmax values for the soluble VSMC and olfactory ANP-Rs were 285 and 30 fmol/mg protein, respectively. Competition binding studies indicated that the VSMC ANP-R bound ANP(99-126), ANP(103-126), and ANP(103-123) with similar affinities, whereas the olfactory ANP-R was much more sensitive to changes in the COOH-terminal structure of the competing peptide. The soluble ANP-Rs from VSMC and olfactory were chromatographically indistinguishable on phenyl-, DEAE-, and wheat germ agglutinin-agarose columns. However, the ANP-Rs could be distinguished using GTP-agarose; the olfactory ANP-R was capable of binding to the resin, whereas the VSMC ANP-R was not. 3. Conclusions. Coupled with other studies, these data suggest that the A10 VSMC ANP-R observed in this study may not be coupled to guanylate cyclase and may represent a receptor serving a clearance function, whereas a significant proportion of the olfactory CNS ANP-R appears to be associated with GTP-binding proteins, likely particulate guanylate cyclase, and probably represents a coupled form of the receptor.},
	address = {United States},
	article-doi = {10.1007/BF00711443},
	author = {Glembotski, C. C. and Wildey, G. M. and Gibson, T. R.},
	completed = {19890615},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1989/03/01 00:00 [entrez]},
	issue = {1},
	journal = {Cellular and molecular neurobiology},
	keywords = {Animals, Cells, Cultured, Kinetics, Muscle, Smooth, Vascular/cytology/*metabolism, Olfactory Bulb/cytology/*metabolism, Rats, Receptors, Atrial Natriuretic Factor, Receptors, Cell Surface/*metabolism},
	language = {eng},
	linking-issn = {0272-4340},
	month = {Mar},
	nlm-unique-id = {8200709},
	owner = {NLM},
	pages = {57--73},
	print-issn = {0272-4340},
	publication-status = {ppublish},
	registry-number = {EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor)},
	revised = {20200304},
	source = {Cell Mol Neurobiol. 1989 Mar;9(1):57-73. doi: 10.1007/BF00711443.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Biochemical studies of soluble atrial natriuretic peptide (ANP) receptors from rat olfactory bulb and vascular smooth muscle cells.},
	title-abbreviation = {Cell Mol Neurobiol},
	volume = {9},
	year = {1989}
}

@article{Glembotski_1988_JBiolChem_263_16073,
	abstract = {Previous studies have demonstrated that primary cultures of cardiac myocytes maintained in a complete serum-free medium contain a precursor to atrial natriuretic factor (ANF-(1-126]. The cultured cells secrete this precursor unless maintained in the presence of glucocorticoids wherein the known circulating form derived from the C-terminal of ANF (ANF-(99-126] is secreted. The present study was designed to determine the fate of the N-terminal region of the ANF precursor during secretion from myocytes maintained in glucocorticoids. A radioimmunoassay (RIA) was developed using synthetic ANF-(1-16); the antiserum demonstrated cross-reactivity toward ANF-(1-126) and ANF-(1-98)-like peptides but did not cross-react with ANF-(99-126). Coupling this RIA with an ANF-(99-126)-specific RIA and reversed phase, size exclusion, and ion exchange high performance liquid chromatography (HPLC), it was shown that primary cultures of atrial myocytes maintained in dexamethasone contained ANF-(1-126) and secreted ANF-(99-126) and a peptide that was chromatographically indistinguishable from ANF-(1-98). Isolated perfused rat hearts were also shown by RIA and HPLC to secrete similar peptides. The primary cells were labeled with [35S]methionine, and the secreted N-terminal ANF-related material was immunoprecipitated with the ANF-(1-16) antiserum. HPLC, tryptic peptide mapping, and radiosequencing demonstrated that this peptide possessed an N-terminal structure identical to that of ANF-(1-126). When the cells were labeled with [3H] leucine and the secreted N-terminal ANF-related material was immunoprecipitated and analyzed by tryptic mapping, it was shown to possess labeled tryptic peptides consistent with the structure of ANF-(1-98). Tryptic mapping of [3H]arginine-labeled N-terminal ANF-related material demonstrated the presence of all peptides consistent with the ANF-(1-98) structure, including ANF-(92-98). These studies demonstrate that primary atrial myocytes contain ANF-(1-126) and in the presence of dexamethasone secrete both ANF-(1-98) and ANF-(99-126), the two major circulating forms of the hormone.},
	address = {United States},
	article-pii = {S0021-9258(18)37560-4},
	author = {Glembotski, C. C. and Dixon, J. E. and Gibson, T. R.},
	completed = {19881202},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1988/11/05 00:00 [entrez]},
	issue = {31},
	journal = {The Journal of biological chemistry},
	keywords = {Amino Acid Sequence, Animals, Atrial Natriuretic Factor/biosynthesis/immunology/*metabolism, Cells, Cultured, Chromatography, High Pressure Liquid, Heart Atria/metabolism, In Vitro Techniques, Molecular Sequence Data, Myocardium/*metabolism, Peptide Fragments/isolation \& purification, Peptide Mapping, *Protein Precursors, Radioimmunoassay, Rats, Thrombin, Trypsin},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Nov},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {16073--81},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.4.21.5 (Thrombin)},
	revised = {20210210},
	source = {J Biol Chem. 1988 Nov 5;263(31):16073-81.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Secretion of atrial natriuretic factor-(1-98) by primary cardiac myocytes.},
	title-abbreviation = {J Biol Chem},
	volume = {263},
	year = {1988}
}

@article{Shields_1988_JBiolChem_263_12619,
	abstract = {Atrial natriuretic factor (ANF) is stored in mammalian atria primarily as ANF-(1-126), the precursor to the known circulating form of the hormone ANF-(99-126). When primary cultures of atrial myocytes were maintained in a complete serum-free medium, they contained and secreted an ANF-(1-126)-like peptide. The addition of dexamethasone to the culture medium, however, resulted in the secretion of a molecule with chromatographic characteristics identical to ANF-(99-126), although the intracellular storage form of ANF was unchanged. Radiosequencing and amino acid analysis confirmed that the cultures maintained in dexamethasone secreted authentic ANF-(99-126). Chronic exposure of the cells to dexamethasone also resulted in a significant increase in the quantity of immunoreactive ANF both contained and secreted by the cultures. Dexamethasone stimulated ANF processing and secretion by atrial cultures in a dose-dependent manner, with an approximate EC50 of 10 nM. This stimulation could be reversed by removing the glucocorticoid from the culture medium. ANF processing was also stimulated by the specific glucocorticoid receptor agonist RU 28362, and both DEX- and RU 28362-stimulated ANF processing was inhibited by the specific glucocorticoid receptor antagonist RU 38486. Ventricular cells, which possess few granules and release ANF in a constitutive fashion, were also capable of processing ANF in a glucocorticoid-dependent fashion. Medium freshly removed from atrial cultures did not convert ANF-(1-126) to ANF-(99-126) nor was exogenous ANF-(1-126) efficiently processed when added to the medium of actively processing cultures. These results indicate that the post-translational processing of ANF-(1-126) to ANF-(99-126) likely occurs within or in close association with the cardiac myocytes and is not dependent on the presence of large quantities of secretory granules. Furthermore, it is apparent that both the expression and the post-translational processing of ANF by cultured cardiac myocytes is specifically regulated by glucocorticoids.},
	address = {United States},
	article-pii = {S0021-9258(18)37799-8},
	author = {Shields, P. P. and Dixon, J. E. and Glembotski, C. C.},
	completed = {19880928},
	grantno = {etc.},
	history = {1988/09/05 00:00 [entrez]},
	issue = {25},
	journal = {The Journal of biological chemistry},
	keywords = {Amino Acids/analysis, Androstanols/pharmacology, Animals, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Chromatography, High Pressure Liquid, Culture Media, Cytoplasmic Granules/physiology, Dexamethasone/pharmacology, Diuretics, Estrenes/pharmacology, Glucocorticoids/*pharmacology, Heart Atria/drug effects/metabolism, Immunohistochemistry, Immunosorbent Techniques, Mifepristone, Myocardium/*metabolism, Peptide Fragments/*metabolism, Protein Processing, Post-Translational, Radioimmunoassay, Rats, Rats, Inbred Strains},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Sep},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {12619--28},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20210210},
	source = {J Biol Chem. 1988 Sep 5;263(25):12619-28.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The secretion of atrial natriuretic factor-(99-126) by cultured cardiac myocytes is regulated by glucocorticoids.},
	title-abbreviation = {J Biol Chem},
	volume = {263},
	year = {1988}
}

@article{Gibson_1988_JNeurosci_8_3067,
	abstract = {Atrial natriuretic peptide (ANP) receptors from A10 cultured vascular smooth muscle cells (VSMC) and rat olfactory bulbs have been solubilized and then pharmacologically and biochemically compared. The dissociation constant for 125I-ANP(99-126) was 12.7 pM for the VSMC-derived receptor and 164 pM for the olfactory receptor. Competition binding between 125I-ANP(99-126) and several unlabeled ANP analogs with the soluble olfactory receptor, demonstrated a rank order potency of ANP(99-126) = ANP(103-126) much greater than ANP(103-123). However, the rank order potency of the soluble VSMC ANP receptor was ANP(99-126) = ANP(103-126) = ANP(103-123). Therefore, the olfactory ANP receptor appears to require the complete COOH-terminal sequence of ANP as compared with the VSMC ANP receptor. When the 2 soluble receptor preparations were applied to a GTP-agarose column, a portion of the olfactory ANP receptor was retained on the column and could be eluted with 5 mM GTP, while the VSMC ANP receptor did not adsorb to the column. Since the olfactory bulb ANP receptor has been shown to contain a binding component of 116 kDa, while the VSMC ANP receptor binding component is 66 kDa, these receptors appear to be similar to the 2 receptor classes described recently in which the 120 kDa receptor that binds GTP is postulated to be coupled to guanylate cyclase, while the 60 kDa receptor does not bind GTP, is not coupled to guanylate cyclase, and may possess a hormone clearance function. Taken together, these data indicate that cyclic GMP appears to be a second messenger for ANP in the brain.},
	article-doi = {10.1523/JNEUROSCI.08-08-03067.1988},
	author = {Gibson, T. R. and Zyskind, A. D. and Glembotski, C. C.},
	completed = {19881007},
	electronic-issn = {1529-2401},
	grantno = {NS 25037/NS/NINDS NIH HHS/United States},
	history = {1988/08/01 00:00 [entrez]},
	issue = {8},
	journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
	keywords = {Animals, Cell Count, Cell Line, Iodine Radioisotopes, Muscle, Smooth, Vascular/cytology/*metabolism, Olfactory Bulb/*metabolism, Rats, Receptors, Atrial Natriuretic Factor, *Receptors, Cell Surface/analysis/*metabolism, Solubility},
	language = {eng},
	linking-issn = {0270-6474},
	month = {Aug},
	nlm-unique-id = {8102140},
	owner = {NLM},
	pages = {3067--73},
	print-issn = {0270-6474},
	publication-status = {ppublish},
	registry-number = {EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor)},
	revised = {20191101},
	source = {J Neurosci. 1988 Aug;8(8):3067-73. doi: 10.1523/JNEUROSCI.08-08-03067.1988.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Characterization of solubilized atrial natriuretic peptide receptors from rat olfactory bulb and A10 cultured smooth muscle cells.},
	title-abbreviation = {J Neurosci},
	volume = {8},
	year = {1988}
}

@article{Shields_1988_JBiolChem_263_8091,
	abstract = {Primary cultures of neonatal rat atrial myocytes were maintained in two different serum-free media for up to 25 days. Reversed-phase high performance liquid chromatography coupled with atrial natriuretic factor (ANF)-specific radioimmunoassay demonstrated that the cultures maintained in our previously described serum-free medium (Glembotski, C.C., and Gibson, T. R. (1985) Biochem. Biophys. Res. Commun. 132, 1008-1017) secreted primarily ANF-(1-126)-like material, whereas those cultures maintained in a different formulation of medium secreted mostly ANF-(99-126)-like material. Cultures that secreted ANF(99-126)-like material were biosynthetically labeled with [35S]cysteine followed by immunoprecipitation of secreted ANF and analysis by reversed-phase, size exclusion, and ion-exchange high performance liquid chromatography. The labeled ANF-(99-126)-like peptide was shown to be chromatographically indistinguishable from other synthetic peptides related to ANF-(99-126). Labeled ANF purified from extracts of the cultured cells was chromatographically indistinguishable from authentic ANF-(1-126), and could be cleaved specifically by thrombin into labeled ANF-(99-126)-like material. These results indicate that primary atrial myocytes maintained under certain serum-free conditions are capable of secreting ANF-related material that is chromatographically indistinguishable from ANF-(99-126), the known circulating form of the hormone. Additional preliminary studies suggest that the presence of glucocorticoids in the culture medium may confer ANF processing ability on cultured myocytes.},
	address = {United States},
	article-pii = {S0021-9258(18)68446-7},
	author = {Shields, P. P. and Glembotski, C. C.},
	completed = {19880713},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1988/06/15 00:00 [entrez]},
	issue = {17},
	journal = {The Journal of biological chemistry},
	keywords = {Animals, Antibodies, Monoclonal, Atrial Natriuretic Factor/*biosynthesis, Cells, Cultured, Chromatography, High Pressure Liquid, Heart Atria/cytology, Myocardium/*metabolism, Protein Precursors/*biosynthesis, *Protein Processing, Post-Translational, Radioimmunoassay, Rats},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {8091--8},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20210210},
	source = {J Biol Chem. 1988 Jun 15;263(17):8091-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The post-translational processing of rat pro-atrial natriuretic factor by primary atrial myocyte cultures.},
	title-abbreviation = {J Biol Chem},
	volume = {263},
	year = {1988}
}

@article{Glembotski_1987_Endocrinology_121_843,
	abstract = {The biochemical and morphological characteristics of primary neonatal rat atrial myocytes were examined in order to establish a model system for future studies of the biosynthesis and secretion of atrial natriuretic peptide (ANP). Preliminary studies demonstrated that the quantity of immunoactive ANP/microgram protein within rat atria increased as a function of age from 2 ng/micrograms in 19 day prenatal animals to 400 ng/micrograms in the adult. Gel filtration, reversed phase HPLC, and ion exchange HPLC indicated that there were similar quantities of immunoactive ANP in the right and left atria at various ages, and that the major molecular form of the peptide in the heart is chromatographically indistinguishable from ANP(1-126). Cultures of dissociated cells were prepared from pooled left and right atria derived from 1 day postnatal animals. A complete serum-free medium was developed which resulted in the maintenance of high levels of immunoactive ANP in the cultures. As determined by RIA, the cellular content of ANP increased in the cultures as a function of time through 7 days in vitro. The quantity of immunoactive ANP in the cultures increased approximately 2- to 3-fold between days 3 and 7. When the cultures that had been maintained for 7 days were submitted to immunocytochemistry using an ANP-specific monoclonal antibody, distinct colonies of spindle-shaped cells stained positively. In situ hybridization, utilizing an 35S-labeled ANP messenger RNA probe, demonstrated that these colonies of myocytes expressed the ANP message. Using quantitative dot-blot hybridization it was shown that the ANP mRNA level increased approximately 50-fold between days 1 and 7 in culture. These studies indicate that the serum-free culture medium allows continued accumulation of both ANP and the ANP message in culture and will provide a useful model system to characterize factors that regulate the biosynthesis and secretion of this hormone.},
	address = {United States},
	article-doi = {10.1210/endo-121-3-843},
	author = {Glembotski, C. C. and Oronzi, M. E. and Li, X. B. and Shields, P. P. and Johnston, J. F. and Kallen, R. G. and Gibson, T. R.},
	completed = {19870928},
	grantno = {NS-25037/NS/NINDS NIH HHS/United States},
	history = {1987/09/01 00:00 [entrez]},
	issue = {3},
	journal = {Endocrinology},
	keywords = {Aging/metabolism, Animals, Antibodies, Monoclonal/immunology, Atrial Natriuretic Factor/*biosynthesis/genetics/immunology, Cells, Cultured, Epitopes/immunology, Female, Heart Atria/metabolism, Histocytochemistry, Immunoassay, Mice, Mice, Inbred BALB C, Myocardium/*metabolism, Nucleic Acid Hybridization, RNA, Messenger/analysis/biosynthesis, Rats},
	language = {eng},
	linking-issn = {0013-7227},
	month = {Sep},
	nlm-unique-id = {0375040},
	owner = {NLM},
	pages = {843--52},
	print-issn = {0013-7227},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20071114},
	source = {Endocrinology. 1987 Sep;121(3):843-52. doi: 10.1210/endo-121-3-843.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The characterization of atrial natriuretic peptide (ANP) expression by primary cultures of atrial myocytes using an ANP-specific monoclonal antibody and an ANP messenger ribonucleic acid probe.},
	title-abbreviation = {Endocrinology},
	volume = {121},
	year = {1987}
}

@article{Shields_1987_BiochemBiophysResCommun_146_547,
	abstract = {Although cultures of neonatal rat atria and ventricles have been widely used to study ANP biosynthesis and secretion, little is known regarding the circulating form of ANP in neonatal animals. To begin to address this issue, we have developed a method for perfusing isolated neonatal rat hearts. Reversed phase-HPLC analysis of the heart effluents coupled with ANP RIA demonstrated that the predominant form of ANP released was chromatographically identical to ANP(99-126). Size exclusion-HPLC confirmed that the secreted ANP was indistinguishable from ANP(99-126). This demonstrated that the neonatal rat heart can efficiently generate and secrete a peptide similar to the circulating form of ANP found in adult rats, and further justifies the use of neonatal rat atria as a source of primary cells for studies of ANP biosynthesis and secretion.},
	address = {United States},
	article-doi = {10.1016/0006-291x(87)90563-8},
	article-pii = {0006-291X(87)90563-8},
	author = {Shields, P. P. and Glembotski, C. C.},
	completed = {19870916},
	grantno = {etc.},
	history = {1987/07/31 00:00 [entrez]},
	issue = {2},
	journal = {Biochemical and biophysical research communications},
	keywords = {Amino Acids/analysis, Animals, Animals, Newborn, Atrial Natriuretic Factor/*metabolism, Cells, Cultured, Chromatography, High Pressure Liquid, Myocardium/*metabolism, Perfusion, Rats, Rats, Inbred Strains},
	language = {eng},
	linking-issn = {0006-291X},
	month = {Jul},
	nlm-unique-id = {0372516},
	owner = {NLM},
	pages = {547--53},
	print-issn = {0006-291X},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190612},
	source = {Biochem Biophys Res Commun. 1987 Jul 31;146(2):547-53. doi: 10.1016/0006-291x(87)90563-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Characterization of the molecular forms of ANP released by perfused neonatal rat heart.},
	title-abbreviation = {Biochem Biophys Res Commun},
	volume = {146},
	year = {1987}
}

@article{Gibson_1987_Endocrinology_120_764,
	abstract = {Atrial myocytes cultured for 7 days in serum-free medium secrete a 15K form of atrial natriuretic peptide (15K ANP), but isolated perfused rat hearts secrete the major circulating form of the hormone, a 3K peptide, 3K ANP. This difference was examined in the present study. 15K ANP was purified from rat atria, and sequencing analysis demonstrated that this atrial-derived ANP possessed an NH2-terminal sequence identical to that of pro-ANP; this is consistent with other reports suggesting that the major form of ANP in the atria is ANP-(1-126). Fresh rat serum was shown to cleave efficiently ANP-(1-126) to form a 3K immunoactive ANP-related peptide. Upon purification and sequencing the identity of this peptide was confirmed as ANP-(99-126); ANP-(99-126) was relatively resistant to further proteolysis by rat serum. To probe further the specificity of the serum conversion, synthetic ANP-(92-126) was used as a substrate; purification and sequencing of the immunoactive product peptide verified its identity as ANP-(99-126). Since purified thrombin and plasma kallikrein both cleaved ANP-(1-126) to 3K ANP-like material, inhibitors of these enzymes were tested for their ability to inhibit the serum cleavage of ANP-(1-126). D-Phe-Phe-Arg-Chloromethylketone (D-Phe-Phe-Arg-CMK) and D-Phe-Pro-Arg-CMK both inhibited serum ANP cleavage by over 90\% at low micromolar concentration. When these inhibitors were added to the isolated heart perfusate, 3K ANP was still released by the atria, indicating that ANP processing occurs in the heart in a region not accessible to the inhibitors (i.e. intracellularly) or that the ANP-processing enzyme(s) is not inhibited by these CMK analogs and is, therefore, not related to serum-derived proteases.},
	address = {United States},
	article-doi = {10.1210/endo-120-2-764},
	author = {Gibson, T. R. and Shields, P. P. and Glembotski, C. C.},
	completed = {19870304},
	grantno = {etc.},
	history = {1987/02/01 00:00 [entrez]},
	issue = {2},
	journal = {Endocrinology},
	keywords = {Amino Acid Sequence, Animals, Atrial Natriuretic Factor/*blood/isolation \& purification/*metabolism, In Vitro Techniques, Male, Molecular Weight, Myocardium/*metabolism, Peptide Fragments/*blood, Perfusion, Radioimmunoassay, Rats, Rats, Inbred Strains},
	language = {eng},
	linking-issn = {0013-7227},
	month = {Feb},
	nlm-unique-id = {0375040},
	owner = {NLM},
	pages = {764--72},
	print-issn = {0013-7227},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20141120},
	source = {Endocrinology. 1987 Feb;120(2):764-72. doi: 10.1210/endo-120-2-764.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The conversion of atrial natriuretic peptide (ANP)-(1-126) to ANP-(99-126) by rat serum: contribution to ANP cleavage in isolated perfused rat hearts.},
	title-abbreviation = {Endocrinology},
	volume = {120},
	year = {1987}
}

@article{Glembotski_1987_AnnNYAcadSci_498_54,
	address = {United States},
	article-doi = {10.1111/j.1749-6632.1987.tb23750.x},
	author = {Glembotski, C. C.},
	completed = {19870831},
	grantno = {NS 20396/NS/NINDS NIH HHS/United States},
	history = {1987/01/01 00:00 [entrez]},
	journal = {Annals of the New York Academy of Sciences},
	keywords = {Animals, Ascorbic Acid/*physiology, Hypothalamus/enzymology, Melanocyte-Stimulating Hormones/*biosynthesis, *Mixed Function Oxygenases, *Multienzyme Complexes, Oxygenases/metabolism, Pituitary Gland/enzymology, Thyrotropin-Releasing Hormone/*biosynthesis},
	language = {eng},
	linking-issn = {0077-8923},
	nlm-unique-id = {7506858},
	owner = {NLM},
	pages = {54--62},
	print-issn = {0077-8923},
	publication-status = {ppublish},
	registry-number = {PQ6CK8PD0R (Ascorbic Acid)},
	revised = {20190616},
	source = {Ann N Y Acad Sci. 1987;498:54-62. doi: 10.1111/j.1749-6632.1987.tb23750.x.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The role of ascorbic acid in the biosynthesis of the neuroendocrine peptides alpha-MSH and TRH.},
	title-abbreviation = {Ann N Y Acad Sci},
	volume = {498},
	year = {1987}
}

@article{Wildey_1986_JNeurosci_6_3767,
	abstract = {Binding sites for 125I-atrial natriuretic peptide (ANP)2 in rat olfactory bulb membranes have been studied using pharmacological and biochemical methods. Various unlabeled ANP-related peptides were tested for the ability to inhibit the binding of the radioligand in membrane binding assays. ANP(92-126) and ANP(99-126) were the most potent inhibitors tested, both exhibiting an IC50 value of 0.40 nM. ANP(103-126) and ANP(103-123) were 3 and 70 times less potent, respectively. ANP(111-126) was unable to inhibit the binding of the radioligand at a concentration of 1 microM. Several peptides unrelated to ANP were unable to inhibit the binding of the radioligand to rat olfactory bulb membranes. Membranes labeled with 125I-ANP were incubated with cross-linking agents and subjected to SDS-PAGE followed by autoradiography. A band possessing an apparent molecular mass of 116 kDa was identified. The labeling of this band was progressively decreased by increasing concentrations of unlabeled ANP(99-126) (IC50 = 0.6 nM) and by several other ANP-related peptides at nanomolar concentrations. For comparison purposes, ANP binding sites in rat aorta membranes were labeled with 125I-ANP and cross-linked using identical techniques. Three bands possessing molecular masses of 120, 72, and 62 kDa were identified. These results indicate that the ANP binding site in rat olfactory bulb membranes displays pharmacological and biochemical properties similar to peripheral ANP receptors.},
	article-doi = {10.1523/JNEUROSCI.06-12-03767.1986},
	author = {Wildey, G. M. and Glembotski, C. C.},
	completed = {19870210},
	electronic-issn = {1529-2401},
	grantno = {SO7-RR-05415-24/RR/NCRR NIH HHS/United States},
	history = {1986/12/01 00:00 [entrez]},
	issue = {12},
	journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
	keywords = {Animals, Aorta/metabolism, Atrial Natriuretic Factor/*metabolism, Binding, Competitive, Cell Membrane/metabolism, *Cross-Linking Reagents, Iodine Radioisotopes, Male, Molecular Weight, Olfactory Bulb/*metabolism, Peptide Fragments/metabolism, Rats, Rats, Inbred Strains, Receptors, Atrial Natriuretic Factor, Receptors, Cell Surface/*metabolism},
	language = {eng},
	linking-issn = {0270-6474},
	month = {Dec},
	nlm-unique-id = {8102140},
	owner = {NLM},
	pages = {3767--76},
	print-issn = {0270-6474},
	publication-status = {ppublish},
	registry-number = {EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor)},
	revised = {20191101},
	source = {J Neurosci. 1986 Dec;6(12):3767-76. doi: 10.1523/JNEUROSCI.06-12-03767.1986.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Cross-linking of atrial natriuretic peptide to binding sites in rat olfactory bulb membranes.},
	title-abbreviation = {J Neurosci},
	volume = {6},
	year = {1986}
}

@article{Gibson_1986_JNeurosci_6_2004,
	abstract = {Atrial natriuretic peptides (ANP) have recently been identified in both heart and CNS. These peptides possess potent natriuretic, diuretic, and vasorelaxant activities, and are all apparently derived from a single prohormone. Specific ANP binding sites have been characterized in the adrenal zona glomerulosa and kidney cortex, and one study reported ANP binding sites in the CNS. However, a detailed examination of the localization of ANP binding sites throughout the brain has not been reported. In this study, quantitative autoradiography was employed to examine the distribution of ANP receptors in the rat CNS. The binding of (3-125I-iodotyrosyl28) rat ANP-28 to binding sites in the rat CNS was saturable, specific for ANP-related peptides, and displayed high affinity (Kd = 600 pM). When the relative concentrations of ANP binding sites were determined throughout the rat brain, the highest levels of ANP binding were localized to the circumventricular organs, including the area postrema and subfornical organ, and the olfactory apparatus. Moderate levels of ANP binding sites were present throughout the midbrain and brain stem, while low levels were found in the forebrain, diencephalon, basal ganglia, cortex, and cerebellum. The presence of ANP binding sites in the subfornical organ and the area postrema, regions considered to be outside the blood-brain barrier, suggests that peripheral ANP levels may regulate some aspects of CNS control of salt and water balance. The possible functions of ANP binding sites in other regions of the rat brain are not known, but, like many other peptides, ANP may act as a neurotransmitter or neuromodulator at these loci.},
	article-doi = {10.1523/JNEUROSCI.06-07-02004.1986},
	author = {Gibson, T. R. and Wildey, G. M. and Manaker, S. and Glembotski, C. C.},
	completed = {19860917},
	electronic-issn = {1529-2401},
	grantno = {etc.},
	history = {1986/07/01 00:00 [entrez]},
	issue = {7},
	journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
	keywords = {Adrenal Glands/*metabolism, Animals, Atrial Natriuretic Factor/*metabolism, Autoradiography, Binding Sites, Central Nervous System/*metabolism, Densitometry, Iodine Radioisotopes, Male, Olfactory Bulb/metabolism, Rats, Rats, Inbred Strains, Statistics as Topic, Tissue Distribution},
	language = {eng},
	linking-issn = {0270-6474},
	month = {Jul},
	nlm-unique-id = {8102140},
	owner = {NLM},
	pages = {2004--11},
	print-issn = {0270-6474},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20191101},
	source = {J Neurosci. 1986 Jul;6(7):2004-11. doi: 10.1523/JNEUROSCI.06-07-02004.1986.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Autoradiographic localization and characterization of atrial natriuretic peptide binding sites in the rat central nervous system and adrenal gland.},
	title-abbreviation = {J Neurosci},
	volume = {6},
	year = {1986}
}

@article{Glembotski_1986_Endocrinology_118_1461,
	abstract = {Previous studies have shown that cultured rat intermediate pituitary lobe cells lose the ability to form ACTH-(1-13)NH2-related molecules (alpha MSH) and instead produce ACTH-(1-14)-related peptides. In vitro studies have shown that peptidylglycine alpha-amidating monooxygenase the enzyme responsible for the conversion of ACTH-(1-14) to ACTH-(1-13)NH2, requires ascorbate, CuSO4, and molecular oxygen as cofactors. In the present study we have demonstrated that cultured intermediate pituitary lobe cells require long term supplementation of the medium with ascorbate for continued production of immunoactive alpha-amidated alpha MSH. When the relative quantities of alpha-amidated and COOH-terminally glycine-extended forms of alpha MSH were assessed in biosynthetic labeling experiments, it was shown that either L-ascorbate or an epimer of the vitamin, D-isoascorbate, was capable of supporting cellular alpha-amidation. However, the potency of isoascorbate was approximately 4- to 5-fold lower than that of ascorbate. The ascorbate-mediated reestablishment of alpha-amidation ability was shown to be dependent on the presence of sodium in the medium; at physiological levels of ascorbate (35 microM), the EC50 for sodium was about 40 mM. Time-course experiments indicated that the time of exposure of the cultured cells to ascorbate could be decreased to as little as 30 min. However, a total incubation time of 6 h was required after such an exposure to convert biosynthetically labeled ACTH-(1-14)-related peptides to labeled ACTH-(1-13)NH2-related peptides. The time course of the effects of ascorbic acid on the reestablishment of alpha-amidation, as well as the relative stereospecificity for L-ascorbic acid and the sodium requirement, are all consistent with the hypothesis that ascorbic acid must be transported into the intermediate pituitary lobe cells to participate in the peptidyl alpha-amidation reaction. Moreover, it is apparent that the length of time required to reestablish alpha-amidation ability (6 h) is a function of transport of the cofactor into the granules, the rate of the peptidylglycine alpha-amidating monooxygenase-catalyzed reaction, or both.},
	address = {United States},
	article-doi = {10.1210/endo-118-4-1461},
	author = {Glembotski, C. C.},
	completed = {19860424},
	grantno = {SO7-RR-05414-23/RR/NCRR NIH HHS/United States},
	history = {1986/04/01 00:00 [entrez]},
	issue = {4},
	journal = {Endocrinology},
	keywords = {Adrenocorticotropic Hormone/metabolism, Animals, Ascorbic Acid/*metabolism, Cells, Cultured, Centrifugation, Density Gradient, Melanocyte-Stimulating Hormones/*metabolism, *Mixed Function Oxygenases, *Multienzyme Complexes, Oxidoreductases Acting on CH-NH Group Donors/*metabolism, Peptide Fragments/metabolism, Pituitary Gland/*enzymology, Rats, Sodium/pharmacology, Subcellular Fractions/metabolism, Time Factors, *alpha-MSH/*analogs \& derivatives},
	language = {eng},
	linking-issn = {0013-7227},
	month = {Apr},
	nlm-unique-id = {0375040},
	owner = {NLM},
	pages = {1461--8},
	print-issn = {0013-7227},
	publication-status = {ppublish},
	registry-number = {PQ6CK8PD0R (Ascorbic Acid)},
	revised = {20131121},
	source = {Endocrinology. 1986 Apr;118(4):1461-8. doi: 10.1210/endo-118-4-1461.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The characterization of the ascorbic acid-mediated alpha-amidation of alpha-melanotropin in cultured intermediate pituitary lobe cells.},
	title-abbreviation = {Endocrinology},
	volume = {118},
	year = {1986}
}

@article{Shields_1986_Endocrinology_118_1452,
	abstract = {Ascorbate is an important cofactor in the biosynthesis of alpha-amidated endocrine and neural peptides. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme responsible for the generation of mature COOH-terminal alpha-amidated peptides from COOH-terminal glycine-extended peptides, and this enzyme requires ascorbate for full activity in vitro. Also, cultured intermediate pituitary lobe cells contain PAM and require ascorbate for the COOH-terminal alpha-amidation of alpha MSH. Since pituitary cells are not capable of synthesizing ascorbate, the ability of the cells to accumulate the cofactor must play an important role in the biosynthesis of alpha-amidated peptides. The AtT20 corticotropic pituitary tumor cell line also contains PAM and a potential site for COOH-terminal alpha-amidation of the pro-ACTH/endorphin-derived hinge peptide and was, thus, used for the study of cellular ascorbate transport. Radiolabeled L-[1-14C]ascorbate ([1-14C]ascorbate) was incubated with the cells under various conditions, and the accumulation of radioactivity by the cells was followed. Reverse phase HPLC was used to identify the integrity of the labeled ascorbate, both intra- and extracellular, during the course of the experiments. The uptake of [1-14C]ascorbate was saturable (Km = 31.5 microM), sodium and temperature dependent, and stereoselective. The products of ascorbate autooxidation, dehydroascorbate and 2,3-diketogulonic acid, did not inhibit [1-14C]ascorbate uptake. To study the presence of ascorbate in the secretory granules, cells were incubated with [1-14C]ascorbate and then induced to secrete with isoproterenol or 8-bromo-cAMP. A 2- to 6-fold stimulation of ACTH secretion over the basal secretion rate was observed; however, the secretion of intracellular [1-14C]ascorbate did not change significantly with stimulation, suggesting that very little of the cellular ascorbate was contained within secretory granules.},
	address = {United States},
	article-doi = {10.1210/endo-118-4-1452},
	author = {Shields, P. P. and Gibson, T. R. and Glembotski, C. C.},
	completed = {19860424},
	grantno = {S07-RR-05415-22/RR/NCRR NIH HHS/United States},
	history = {1986/04/01 00:00 [entrez]},
	issue = {4},
	journal = {Endocrinology},
	keywords = {2, 3-Diketogulonic Acid/analysis, 8-Bromo Cyclic Adenosine Monophosphate/pharmacology, Adrenocorticotropic Hormone/metabolism, Animals, Ascorbic Acid/*metabolism, Biological Transport, Cell Line, Chromatography, High Pressure Liquid, Dehydroascorbic Acid/analysis, Dose-Response Relationship, Drug, Isoproterenol/pharmacology, Kinetics, Mice, *Mixed Function Oxygenases, *Multienzyme Complexes, Osmolar Concentration, Oxidoreductases Acting on CH-NH Group Donors/metabolism, Pituitary Neoplasms/*metabolism, Pro-Opiomelanocortin/metabolism, Sodium/metabolism, Temperature},
	language = {eng},
	linking-issn = {0013-7227},
	month = {Apr},
	nlm-unique-id = {0375040},
	owner = {NLM},
	pages = {1452--60},
	print-issn = {0013-7227},
	publication-status = {ppublish},
	registry-number = {Y2Z3ZTP9UM (Dehydroascorbic Acid)},
	revised = {20131121},
	source = {Endocrinology. 1986 Apr;118(4):1452-60. doi: 10.1210/endo-118-4-1452.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Ascorbate transport by AtT20 mouse pituitary corticotropic tumor cells: uptake and secretion studies.},
	title-abbreviation = {Endocrinology},
	volume = {118},
	year = {1986}
}

@article{Stone_1986_BiochemBiophysResCommun_134_1022,
	abstract = {Acid extracts of rat anterior uvea and retina contain immunoactive atrial natriuretic peptide. Gel filtration chromatography demonstrates that the major forms of the uveal and retinal material have approximate molecular weights of 2400 and 1750 daltons respectively, similar in size to the hypothalamic form of the peptide but clearly distinguishable from the larger, cardiac form. When further analyzed by RP-HPLC, the immunoactive material from both ocular tissues elutes at a position similar to atrial natriuretic peptide-28, again distinguishing the ocular and cardiac forms of immunoactive material. These results suggest potential roles for atrial natriuretic peptide both in ocular vegetative physiology and in retinal function.},
	address = {United States},
	article-doi = {10.1016/s0006-291x(86)80523-x},
	article-pii = {S0006-291X(86)80523-X},
	author = {Stone, R. A. and Glembotski, C. C.},
	completed = {19860324},
	grantno = {SO7-RR-05415-23/RR/NCRR NIH HHS/United States},
	history = {1986/01/29 00:00 [entrez]},
	issue = {2},
	journal = {Biochemical and biophysical research communications},
	keywords = {Animals, Atrial Natriuretic Factor/immunology/*metabolism, Chromatography, High Pressure Liquid, Eye/*metabolism, Molecular Weight, Radioimmunoassay, Rats, Retina/metabolism, Urea/metabolism},
	language = {eng},
	linking-issn = {0006-291X},
	month = {Jan},
	nlm-unique-id = {0372516},
	owner = {NLM},
	pages = {1022--8},
	print-issn = {0006-291X},
	publication-status = {ppublish},
	registry-number = {8W8T17847W (Urea)},
	revised = {20190612},
	source = {Biochem Biophys Res Commun. 1986 Jan 29;134(2):1022-8. doi: 10.1016/s0006-291x(86)80523-x.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Immunoactive atrial natriuretic peptide in the rat eye: molecular forms in anterior uvea and retina.},
	title-abbreviation = {Biochem Biophys Res Commun},
	volume = {134},
	year = {1986}
}

@article{Glembotski_1985_BiochemBiophysResCommun_132_1008,
	abstract = {Primary cultures of atrial myocytes were prepared from newborn rats and maintained for 8 days in complete serum-free medium. The culture content of immunoactive atrial natriuretic peptide (ANP) increased from 10 to 25 ng/culture during this time. The cells released immunoactive ANP at a rate of 2 to 3\% of culture content per hour in a linear fashion for at least 6 hours. When analyzed by gel filtration the major immunoactive material released by and contained within the cells displayed a molecular weight of approximately 15,000 daltons. The medium and cellular ANP-related peptides were further shown to be indistinguishable by reversed-phase HPLC. When the 15,000 dalton material was incubated with rat serum it was converted to ANP-related material possessing a molecular weight of approximately 3,000 daltons. These results suggest that under basal conditions, atrial myocytes release a large molecular weight form of ANP that is converted in the circulation to a low molecular weight form of ANP, which has been previously identified in plasma.},
	address = {United States},
	article-doi = {10.1016/0006-291x(85)91907-2},
	article-pii = {0006-291X(85)91907-2},
	author = {Glembotski, C. C. and Gibson, T. R.},
	completed = {19860108},
	grantno = {S07-RR-05415-24/RR/NCRR NIH HHS/United States},
	history = {1985/11/15 00:00 [entrez]},
	issue = {3},
	journal = {Biochemical and biophysical research communications},
	keywords = {Animals, Atrial Natriuretic Factor/*analysis/immunology/metabolism, Cells, Cultured, Molecular Weight, Myocardium/*analysis/metabolism, Rats},
	language = {eng},
	linking-issn = {0006-291X},
	month = {Nov},
	nlm-unique-id = {0372516},
	owner = {NLM},
	pages = {1008--17},
	print-issn = {0006-291X},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190612},
	source = {Biochem Biophys Res Commun. 1985 Nov 15;132(3):1008-17. doi: 10.1016/0006-291x(85)91907-2.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Molecular forms of immunoactive atrial natriuretic peptide released from cultured rat atrial myocytes.},
	title-abbreviation = {Biochem Biophys Res Commun},
	volume = {132},
	year = {1985}
}

@article{Glembotski_1985_ArchBiochemBiophys_241_673,
	abstract = {In previous studies we have demonstrated a secretory granule-associated peptide alpha-amidation activity in rat anterior, intermediate, and posterior pituitary. This activity is capable of converting 125I-labeled synthetic D-Tyr-Val-Gly to labeled D-Tyr-Val-NH2, and requires ascorbic acid, CuSO4, and molecular oxygen for optimal activity. Because of the requirement for peptides with COOH-terminal glycine residues, and cofactor requirements similar to monooxygenases such as dopamine beta-monooxygenase, we have proposed that the alpha-amidating enzyme be named peptidylglycine alpha-amidating monooxygenase, or PAM. The present study focused on (i) verifying that PAM could utilize a physiologically relevant peptide substrate, and (ii) demonstrating the retention of the cofactor requirements with purification of PAM. PAM (Mr = 50,000) was partially purified from rat anterior pituitary secretory granules and was shown to be capable of converting alpha-N-acetyl-ACTH(1-14) to alpha-N-acetyl-ACTH(1-13)NH2 (alpha-melanocyte stimulating hormone) and ACTH(9-14) to ACTH(9-13)NH2. The optimal rates for these conversions were dependent on ascorbic acid and CuSO4. Kinetic analyses, using the model compound D-Tyr-Val-Gly as the peptide substrate, demonstrated that, compared to the crude granule extract, the partially purified enzyme displayed increased apparent affinities for both the peptide substrate and ascorbate. These analyses also showed that the Km for D-Tyr-Val-Gly was dependent on the concentration of ascorbate, while the Km for ascorbate was constant over a wide range of D-Tyr-Val-Gly concentrations. The results presented here indicate that PAM can alpha-amidate physiologically relevant peptides related to alpha MSH, and performs the reaction in an ascorbate-dependent fashion. Retention of the ascorbate and copper requirements with purification further support the hypothesis that these cofactors are important requirements for the COOH-terminal alpha-amidation of neuro and endocrine peptides.},
	address = {United States},
	article-doi = {10.1016/0003-9861(85)90594-6},
	article-pii = {0003-9861(85)90594-6},
	author = {Glembotski, C. C.},
	completed = {19851017},
	grantno = {SO7-RR-05415-22/RR/NCRR NIH HHS/United States},
	history = {1985/09/01 00:00 [entrez]},
	issue = {2},
	journal = {Archives of biochemistry and biophysics},
	keywords = {Adrenocorticotropic Hormone/metabolism, Animals, Ascorbic Acid/pharmacology, Copper/pharmacology, Copper Sulfate, Cytoplasmic Granules/*enzymology, Kinetics, Male, *Mixed Function Oxygenases, *Multienzyme Complexes, Oxidoreductases Acting on CH-NH Group Donors/analysis/*isolation \& purification, Pituitary Gland, Anterior/*enzymology, Rats, Rats, Inbred Strains, Substrate Specificity},
	language = {eng},
	linking-issn = {0003-9861},
	month = {Sep},
	nlm-unique-id = {0372430},
	owner = {NLM},
	pages = {673--83},
	print-issn = {0003-9861},
	publication-status = {ppublish},
	registry-number = {PQ6CK8PD0R (Ascorbic Acid)},
	revised = {20190628},
	source = {Arch Biochem Biophys. 1985 Sep;241(2):673-83. doi: 10.1016/0003-9861(85)90594-6.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Further characterization of the peptidyl alpha-amidating enzyme in rat anterior pituitary secretory granules.},
	title-abbreviation = {Arch Biochem Biophys},
	volume = {241},
	year = {1985}
}

@article{Gibson_1985_Peptides_6_615,
	abstract = {ACTH(1-8) and ACTH(9-13)NH2 were used as potential enzyme inhibitors to begin examining the relationship between the acetylation of ACTH- and beta-endorphin-related peptides. ACTH(1-8) was a potent inhibitor of the acetylation of both ACTH- and beta-endorphin-related peptides, whereas ACTH(9-13)NH2 was an effective inhibitor only of the acetylation of ACTH-related substrates. This inhibition pattern indicated that there may be an unusual interaction between some ACTH- and beta-endorphin-related peptides as substrates for the acetyltransferase. Utilizing HPLC to separate ACTH- and beta-endorphin-related peptides present in the same reaction mixture, ACTH(1-14) and beta-endorphin(1-27) at Km and saturating concentrations were used as substrates to examine the ability of one peptide substrate to affect the acetylation of the other. It was observed that the acetylation of ACTH(1-14), even at Km concentration, was relatively unaffected by the presence of beta-endorphin(1-27). However, the acetylation of beta-endorphin(1-27) was significantly reduced by the presence of ACTH(1-14). This preferential acetylation of ACTH-related peptides over the acetylation of beta-endorphin-related peptides might have physiological importance under some conditions.},
	address = {United States},
	article-doi = {10.1016/0196-9781(85)90162-7},
	article-pii = {0196-9781(85)90162-7},
	author = {Gibson, T. R. and Glembotski, C. C.},
	completed = {19851230},
	grantno = {S07-RR-05415-23/RR/NCRR NIH HHS/United States},
	history = {1985/07/01 00:00 [entrez]},
	issue = {4},
	journal = {Peptides},
	keywords = {Acetylation, Acetyltransferases/*metabolism, Adrenocorticotropic Hormone/analogs \& derivatives, Animals, Cell Fractionation, Cytoplasmic Granules/*enzymology, Endorphins/*metabolism, Kinetics, Melanocyte-Stimulating Hormones/*metabolism, Pituitary Gland/*enzymology, Rats, Substrate Specificity, beta-Endorphin},
	language = {eng},
	linking-issn = {0196-9781},
	month = {Jul-Aug},
	nlm-unique-id = {8008690},
	owner = {NLM},
	pages = {615--20},
	print-issn = {0196-9781},
	publication-status = {ppublish},
	registry-number = {EC 2.3.1.- (Acetyltransferases)},
	revised = {20190818},
	source = {Peptides. 1985 Jul-Aug;6(4):615-20. doi: 10.1016/0196-9781(85)90162-7.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Acetylation of alpha MSH and beta-endorphin by rat neurointermediate pituitary secretory granule-associated acetyltransferase.},
	title-abbreviation = {Peptides},
	volume = {6},
	year = {1985}
}

@article{Glembotski_1985_BiochemBiophysResCommun_129_671,
	abstract = {Acid extracts of rat hypothalamus and atrium were prepared by a procedure previously shown to minimize proteolytic degradation of peptides. The majority of the immunoactive material in the atrial extracts had a molecular weight of approximately 9,000 to 15,000 daltons, while that in the hypothalamic extracts had a molecular weight of about 1,500 to 1,800 daltons. The major molecular weight forms of atrial natriuretic peptide from each extract were further distinguishable when analyzed by RP-HPLC. These results suggest that small peptides such as atriopeptins I, II, and III, may not be authentic post-translational processing products in the atrium, and that the hypothalamus and atrium may differentially cleave pro-atrial natriuretic peptide to form tissue-specific products.},
	address = {United States},
	article-doi = {10.1016/0006-291x(85)91944-8},
	article-pii = {0006-291X(85)91944-8},
	author = {Glembotski, C. C. and Wildey, G. M. and Gibson, T. R.},
	completed = {19850809},
	grantno = {SO7-RR-05415-23/RR/NCRR NIH HHS/United States},
	history = {1985/06/28 00:00 [entrez]},
	issue = {3},
	journal = {Biochemical and biophysical research communications},
	keywords = {Animals, Atrial Natriuretic Factor, Chromatography, High Pressure Liquid, Heart Atria/analysis, Hypothalamus/*analysis, Molecular Weight, Muscle Proteins/*analysis, Myocardium/*analysis, Protein Processing, Post-Translational, Radioimmunoassay, Rats},
	language = {eng},
	linking-issn = {0006-291X},
	month = {Jun},
	nlm-unique-id = {0372516},
	owner = {NLM},
	pages = {671--8},
	print-issn = {0006-291X},
	publication-status = {ppublish},
	registry-number = {85637-73-6 (Atrial Natriuretic Factor)},
	revised = {20190612},
	source = {Biochem Biophys Res Commun. 1985 Jun 28;129(3):671-8. doi: 10.1016/0006-291x(85)91944-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Molecular forms of immunoactive atrial natriuretic peptide in the rat hypothalamus and atrium.},
	title-abbreviation = {Biochem Biophys Res Commun},
	volume = {129},
	year = {1985}
}

@article{Glembotski_1984_JBiolChem_259_13041,
	abstract = {Rat intermediate pituitary cells in primary culture display a time-dependent loss of the ability to produce COOH-terminally alpha-amidated alpha MSH (Glembotski, C.C., Eipper, B.A., and Mains, R.E. (1983) J. Biol. Chem. 258, 7299-7304). Instead of des-, mono-, and diacetyl-adrenocorticotropic hormone(ACTH) (1-13)NH2, the cells produce des-, mono-, and diacetyl-ACTH(1-14)OH. Since the pituitary secretory granule-associated alpha-amidation enzyme requires copper and ascorbic acid for optimal activity (Eipper, B.A., Mains, R.E., and Glembotski, C. C. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 5144-5148), these cofactors were added to cultures of intermediate pituitary cells in an attempt to reverse the loss of peptide alpha-amidation ability. When the cultures were supplemented with up to 100 microM cooper (II) there was very little change in the ability to alpha-amidate alpha-melanotropin. Ascorbic acid at concentrations of up to 500 microM resulted in a dramatic increase in the ability of the cells to form the alpha-amidated peptide. Various combinations of ascorbic acid and copper additions indicated that a relatively short exposure (hours) to ascorbic acid produced the maximal response. Ascorbic acid displayed a dose-dependent effect on the alpha-amidation ability with a half-optimal concentration of about 25 microM. Pulse-chase labeling experiments demonstrated the ascorbic acid-dependent conversion of labeled ACTH(1-14)OH-related peptides to ACTH(1-13)NH2-related peptides. These results correlate with the ascorbic acid requirement of the pituitary alpha-amidation enzyme and demonstrate that the direct precursors to ACTH(1-13)NH2-related peptides are ACTH(1-14)OH-related peptides. Combined with our previous data, the present studies support the notion that a wide range of neuro- and endocrine peptides become alpha-amidated in a similar ascorbic acid-dependent manner.},
	address = {United States},
	article-pii = {S0021-9258(18)90653-8},
	author = {Glembotski, C. C.},
	completed = {19841212},
	grantno = {SO7-RR-05415-22/RR/NCRR NIH HHS/United States},
	history = {1984/11/10 00:00 [entrez]},
	issue = {21},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/metabolism, Amides/analysis, Animals, Ascorbic Acid/*pharmacology, Cells, Cultured, Kinetics, Male, Melanocyte-Stimulating Hormones/biosynthesis/*metabolism, Pituitary Gland/drug effects/*metabolism, Rats, Thiourea/pharmacology},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Nov},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {13041--8},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {PQ6CK8PD0R (Ascorbic Acid)},
	revised = {20210210},
	source = {J Biol Chem. 1984 Nov 10;259(21):13041-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {The alpha-amidation of alpha-melanocyte stimulating hormone in intermediate pituitary requires ascorbic acid.},
	title-abbreviation = {J Biol Chem},
	volume = {259},
	year = {1984}
}

@article{Glembotski_1984_JBiolChem_259_6385,
	abstract = {A secretory granule associated enzymatic activity from the rat anterior pituitary that can convert the synthetic peptide D-Tyr-Val-Gly into D-Tyr-Val-NH2 is described. Due to the presence of inhibitory activity in the cytosol and rough endoplasmic reticulum/Golgi apparatus fractions, the alpha-amidation activity is barely detectable in crude rat anterior pituitary homogenates. The alpha-amidation activity was primarily soluble, displayed a pH optimum of about 7.0, and showed a requirement for molecular oxygen. The activity was stimulated 7-fold by the addition of optimal concentrations of copper. Of the cofactors tested, only reduced ascorbate produced a severalfold stimulation of activity. Studies with varied D-Tyr-Val-Gly or varied monoiodo-D-Tyr-Val-Gly demonstrate Michaelis Menten kinetics with indistinguishable kinetic constants for both peptides. Upon addition of ascorbate, the apparent Km and Vmax for the synthetic substrate, as estimated from Lineweaver-Burk and Eadie-Hofstee plots, increased by 30- and 60-fold, respectively. Several alpha-melanotropin- and gamma-melanotropin-related peptides with COOH-terminal glycine residues were effective competitive inhibitors of the reaction while the corresponding alpha-amidated peptides were very poor inhibitors. The rat anterior pituitary alpha-amidation activity appears to be very similar to the alpha-amidation activity in rat intermediate and neural pituitary, and mouse anterior pituitary tumor cells.},
	address = {United States},
	article-pii = {S0021-9258(20)82153-X},
	author = {Glembotski, C. C. and Eipper, B. A. and Mains, R. E.},
	completed = {19840702},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1984/05/25 00:00 [entrez]},
	issue = {10},
	journal = {The Journal of biological chemistry},
	keywords = {Amides/*metabolism, Animals, Copper/pharmacology, Cytoplasmic Granules/*enzymology, Kinetics, Mice, Peptides/*metabolism, Pituitary Gland, Anterior/*enzymology, Pituitary Gland, Posterior/enzymology, Protein Processing, Post-Translational, Rats, Subcellular Fractions/enzymology, Substrate Specificity},
	language = {eng},
	linking-issn = {0021-9258},
	month = {May},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {6385--92},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {789U1901C5 (Copper)},
	revised = {20210210},
	source = {J Biol Chem. 1984 May 25;259(10):6385-92.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Characterization of a peptide alpha-amidation activity from rat anterior pituitary.},
	title-abbreviation = {J Biol Chem},
	volume = {259},
	year = {1984}
}

@article{Mains_1984_Endocrinology_114_1522,
	abstract = {Mouse anterior pituitary corticotropic tumor cells (AtT-20/D-16v) were homogenized and subjected to subcellular fractionation. A secretory granule associated enzyme activity was detected which could convert D-Tyr-Val-Gly into D-Tyr-Val-NH2. The enzyme activity was dependent on the presence of molecular oxygen, copper ions, and reduced ascorbate. Potent endogenous inhibitors of the enzyme obscured the activity unless appropriate levels of copper ions were added. The production of radiolabeled D-Tyr-Val-NH2 from labeled D-Tyr-Val-Gly was inhibited by a wide variety of peptides possessing COOH-terminal glycine residues but not by a number of other peptides, suggesting that many peptides with COOH-terminal glycine residues can function as substrates in the alpha-amidation reaction. Kinetic studies with varied concentrations of D-Tyr-Val-Gly demonstrated Michaelis-Menten kinetics; both the Km for D-Tyr-Val-Gly and maximum velocity (Vmax) increased upon addition of ascorbate to the reaction. Under optimized assay conditions, the secretory granule pool contains enough alpha-amidation activity to alpha-amidate all the relevant peptides in granules in a small fraction of the total time required for complete biosynthetic processing. Secretion of alpha-amidation activity was stimulated along with secretion of pro-ACTH/endorphin-derived peptides upon addition of synthetic corticotropin releasing factor or 8-bromo-cAMP.},
	address = {United States},
	article-doi = {10.1210/endo-114-5-1522},
	author = {Mains, R. E. and Glembotski, C. C. and Eipper, B. A.},
	completed = {19840530},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1984/05/01 00:00 [entrez]},
	issue = {5},
	journal = {Endocrinology},
	keywords = {Amides/*metabolism, Animals, Ascorbic Acid/metabolism, Cytoplasmic Granules/*enzymology, Flavin Mononucleotide/metabolism, Flavin-Adenine Dinucleotide/metabolism, Kinetics, Mice, Oligopeptides/metabolism, Pituitary Gland, Anterior/*ultrastructure, Pituitary Neoplasms/*enzymology, *Protein Processing, Post-Translational},
	language = {eng},
	linking-issn = {0013-7227},
	month = {May},
	nlm-unique-id = {0375040},
	owner = {NLM},
	pages = {1522--30},
	print-issn = {0013-7227},
	publication-status = {ppublish},
	registry-number = {PQ6CK8PD0R (Ascorbic Acid)},
	revised = {20170928},
	source = {Endocrinology. 1984 May;114(5):1522-30. doi: 10.1210/endo-114-5-1522.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Peptide alpha-amidation activity in mouse anterior pituitary AtT-20 cell granules: properties and secretion.},
	title-abbreviation = {Endocrinology},
	volume = {114},
	year = {1984}
}

@article{Eipper_1983_Peptides_4_921,
	abstract = {A secretory granule-associated enzymatic activity that converts mono-[125I]-D-Tyr-Val-Gly into mono-[125I]-D-Tyr-Val-NH2 has been studied. The activity is primarily soluble and shows optimal activity at pH 7 to pH 8. Amidation activity was stimulated 9-fold by addition of optimal amounts of copper (3 microM). In the presence of optimal copper, ascorbate stimulated the reaction 7-fold; none of the other reduced or oxidized cofactors tested was as effective. Taking into account the dependence of the reaction on ascorbate and molecular oxygen and the production of glyoxylate [2], it is suggested that the alpha-amidation enzyme is a monooxygenase. Lineweaver Burk plots with D-Tyr-Val-Gly as the varied substrate demonstrated Michelis-Menten type kinetics with the values of Km and Vmax increasing with the addition of ascorbate to the assay. A variety of peptides ending with a COOH-terminal Gly residue act as inhibitors of the reaction. Two synthetic peptides, gamma 2MSH and ACTH(1-14), with carboxyl termini similar to the presumed physiological substrates for the enzyme, act as competitive inhibitors with similar K1 values. It is likely that this secretory granule alpha-amidation activity is involved in the physiological biosynthetic alpha-amidation of a wide range of bioactive peptides.},
	address = {United States},
	article-doi = {10.1016/0196-9781(83)90091-8},
	article-pii = {0196-9781(83)90091-8},
	author = {Eipper, B. A. and Glembotski, C. C. and Mains, R. E.},
	completed = {19840511},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1983/11/01 00:00 [entrez]},
	issue = {6},
	journal = {Peptides},
	keywords = {Animals, Cattle, Copper/pharmacology, Copper Sulfate, Cytoplasmic Granules/*enzymology, Iodine Radioisotopes, Kinetics, *Mixed Function Oxygenases, *Multienzyme Complexes, Nerve Tissue Proteins/pharmacology, Oligopeptides/pharmacology, Oxidoreductases Acting on CH-NH Group Donors/isolation \& purification/*metabolism, Pituitary Gland/*enzymology},
	language = {eng},
	linking-issn = {0196-9781},
	month = {Nov-Dec},
	nlm-unique-id = {8008690},
	owner = {NLM},
	pages = {921--8},
	print-issn = {0196-9781},
	publication-status = {ppublish},
	registry-number = {LRX7AJ16DT (Copper Sulfate)},
	revised = {20190818},
	source = {Peptides. 1983 Nov-Dec;4(6):921-8. doi: 10.1016/0196-9781(83)90091-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Bovine intermediate pituitary alpha-amidation enzyme: preliminary characterization.},
	title-abbreviation = {Peptides},
	volume = {4},
	year = {1983}
}

@article{Eipper_1983_PNAS_80_5144,
	abstract = {An enzymatic activity capable of producing an alpha-amidated peptide product from its glycine-extended precursor has been identified in secretory granules of rat anterior, intermediate, and neural pituitary and bovine intermediate pituitary. High levels of endogenous inhibitors of this alpha-amidation activity have also been found in tissue homogenates. The alpha-amidation activity is totally inhibited by addition of divalent metal ion chelators such as diethyldithiocarbamate, o-phenanthroline, and EDTA; alpha-amidation activity is restored to above control levels upon addition of copper. The alpha-amidation reaction requires the presence of molecular oxygen. Of the various cofactors tested, ascorbic acid was the most potent stimulator of alpha-amidation. The alpha-amidation activity has a neutral pH optimum and is primarily soluble following several cycles of freezing and thawing. Kinetic studies with the bovine intermediate pituitary granule-associated activity demonstrated a linear Lineweaver-Burk plot when D-Tyr-Val-Gly was the varied substrate; the apparent Km and Vmax varied with the concentration of ascorbic acid. The substrate specificity of the alpha-amidation activity appears to be quite broad; the conversion of D-Tyr-Val-Gly into D-Tyr-Val-NH2 is inhibited by the addition of a variety of glycine-extended peptides.},
	article-doi = {10.1073/pnas.80.16.5144},
	author = {Eipper, B. A. and Mains, R. E. and Glembotski, C. C.},
	completed = {19830920},
	electronic-issn = {1091-6490},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1983/08/01 00:00 [entrez]},
	issue = {16},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	keywords = {Aerobiosis, Amides/metabolism, Animals, Ascorbic Acid/*pharmacology, Cattle, Chelating Agents/pharmacology, Copper/*pharmacology, *Glycine, Kinetics, Male, Oxygen, Peptides/*metabolism, Pituitary Gland/*enzymology, Pituitary Gland, Anterior/enzymology, Pituitary Gland, Posterior/enzymology, Protein Processing, Post-Translational, Rats, Substrate Specificity, Tissue Distribution},
	language = {eng},
	linking-issn = {0027-8424},
	month = {Aug},
	nlm-unique-id = {7505876},
	owner = {NLM},
	pages = {5144--8},
	print-issn = {0027-8424},
	publication-status = {ppublish},
	registry-number = {TE7660XO1C (Glycine)},
	revised = {20190501},
	source = {Proc Natl Acad Sci U S A. 1983 Aug;80(16):5144-8. doi: 10.1073/pnas.80.16.5144.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid.},
	title-abbreviation = {Proc Natl Acad Sci U S A},
	volume = {80},
	year = {1983}
}

@article{Glembotski_1983_JBiolChem_258_7299,
	abstract = {The structures of the altered alpha-melanotropin (alpha MSH or alpha-N-acetyl-ACTH(1-13)NH2)-related molecules produced by cultured rat intermediate pituitary cells were investigated. Peptide analyses demonstrated that the alpha MSH-related molecules produced by acutely prepared intermediate pituitary cells were primarily des-, mono-, and diacetylated ACTH(1-13)NH2; in contrast, longer term cultures produced primarily des-, mono-, and diacetylated ACTH(1-14)OH. No significant amount of labeled ACTH(1-13)OH-related material was observed under any incubation conditions. Intermediate pituitary cells in culture stopped producing alpha-amidated alpha MSH-related molecules with a half-time of approximately 15 to 18 h; instead, ACTH(1-14)OH-related molecules were synthesized. In several pulse-chase experiments, performed under conditions where cultured intermediate pituitary cells were capable of synthesizing alpha MSH-related molecules terminating in -Val13-NH2, labeled molecules ending in -Val13-Gly14-OH were not found to give rise to major amounts of labeled molecules ending in -Val13-NH2. This failure to observe conversion of glycine-extended molecules into alpha-amidated products was not due to selective secretion from the cells, since the acetylation and amidation states of labeled molecules that were secreted under basal conditions reflected those of the molecules stored in the cells, and the basal rate of secretion was very low.},
	address = {United States},
	article-pii = {S0021-9258(18)32177-X},
	author = {Glembotski, C. C. and Eipper, B. A. and Mains, R. E.},
	completed = {19830811},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1983/06/25 00:00 [entrez]},
	issue = {12},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/isolation \& purification/*metabolism, Animals, Cells, Cultured, Kinetics, Male, Melanocyte-Stimulating Hormones/*biosynthesis, Peptide Fragments/analysis/isolation \& purification/*metabolism, Pituitary Gland/*metabolism, Rats, Structure-Activity Relationship, Trypsin},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7299--304},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.4.21.4 (Trypsin)},
	revised = {20210210},
	source = {J Biol Chem. 1983 Jun 25;258(12):7299-304.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Adrenocorticotropin(1-14)OH-related molecules in primary cultures of rat intermediate pituitary cells. Identification and role in the biosynthesis of alpha-melanotropin.},
	title-abbreviation = {J Biol Chem},
	volume = {258},
	year = {1983}
}

@article{Eipper_1983_JBiolChem_258_7292,
	abstract = {The production of alpha-melanotropin (alpha-N-acetyl-ACTH(1-13)NH2 (alpha MSH) in rat intermediate pituitary was investigated using reverse phase high performance liquid chromatography, immunoassays, and biosynthetic labeling. Extracts of rat intermediate pituitary contain primarily alpha-N,O-diacetyl-ACTH(1-13)NH2, with smaller amounts of des- and monoacetyl-ACTH(1-13)NH2. No significant amount of ACTH(1-14)OH- or ACTH(1-13)OH-related material was observed. Analysis of the newly synthesized alpha MSH-sized peptides produced by freshly prepared rat intermediate pituitary cell suspensions revealed labeled peptides co-migrating primarily with des-, mono-, and diacetyl-ACTH(1-13)NH2. In contrast, when extracts of 2-week-old intermediate pituitary cultures were analyzed, the major peak of material detected with the general NH2-terminal ACTH antiserum eluted at the position expected for alpha-N,O-diacetyl-ACTH(1-14)OH; smaller amounts of material co-migrating with des- and monoacetyl-ACTH(1-14)OH were also detected. Analysis of the newly synthesized alpha MSH-sized peptides produced by 16-day-old cultures of intermediate pituitary cells revealed labeled peptides co-migrating with des-, mono-, and diacetyl-ACTH(1-14)OH. Thus, rat intermediate pituitary cells in culture maintain the ability to perform several major proteolytic cleavages of pro-ACTH/endorphin as well as the ability to alpha-N-acetylate alpha MSH and beta-endorphin, but selectively lose the ability to alpha-amidate the carboxyl terminus of alpha MSH.},
	address = {United States},
	article-pii = {S0021-9258(18)32176-8},
	author = {Eipper, B. A. and Glembotski, C. C. and Mains, R. E.},
	completed = {19830811},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1983/06/25 00:00 [entrez]},
	issue = {12},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/analysis, Amides, Animals, Antigen-Antibody Complex, Cells, Cultured, Immune Sera, Male, Melanocyte-Stimulating Hormones/analogs \& derivatives/analysis/*metabolism, Pituitary Gland/*metabolism, Rats, Structure-Activity Relationship},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jun},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7292--8},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {9002-79-3 (Melanocyte-Stimulating Hormones)},
	revised = {20210210},
	source = {J Biol Chem. 1983 Jun 25;258(12):7292-8.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Selective loss of alpha-melanotropin-amidating activity in primary cultures of rat intermediate pituitary cells.},
	title-abbreviation = {J Biol Chem},
	volume = {258},
	year = {1983}
}

@article{Glembotski_1982_JBiolChem_257_10501,
	address = {United States},
	article-pii = {S0021-9258(18)34046-8},
	author = {Glembotski, C. C.},
	completed = {19821021},
	grantno = {etc.},
	history = {1982/09/10 00:00 [entrez]},
	issue = {17},
	journal = {The Journal of biological chemistry},
	keywords = {Acetylation, Acetyltransferases/*metabolism, Adrenocorticotropic Hormone, Animals, Cattle, Cell Fractionation, Cells, Cultured, Centrifugation, Density Gradient, Endorphins/*metabolism, Kinetics, Melanocyte-Stimulating Hormones/*metabolism, N-Terminal Acetyltransferases, Pituitary Gland/*enzymology, Rats, Subcellular Fractions/metabolism, beta-Endorphin},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Sep},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {10501--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 2.3.1.88 (N-Terminal Acetyltransferases)},
	revised = {20210210},
	source = {J Biol Chem. 1982 Sep 10;257(17):10501-9.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Characterization of the peptide acetyltransferase activity in bovine and rat intermediate pituitaries responsible for the acetylation of beta-endorphin and alpha-melanotropin.},
	title-abbreviation = {J Biol Chem},
	volume = {257},
	year = {1982}
}

@article{Glembotski_1982_JBiolChem_257_10493,
	abstract = {The subcellular site of the further processing (NH2-terminal acetylation and COOH-terminal proteolysis) of beta-endorphin-sized molecules in the rat intermediate pituitary has been studied. Rat intermediate pituitary primary cultures that had been incubated in radioactively labeled amino acids were homogenized and the secretory granule fraction was separated from the rough endoplasmic reticulum/Golgi apparatus fraction. The labeled beta-endorphin-sized molecules in each subcellular fraction were analyzed by immunoprecipitation, gel filtration chromatography, and ion exchange chromatography. A large percentage of the labeled beta-endorphin-sized molecules became NH2 terminally acetylated after becoming associated with the secretory granule fraction; most of the further COOH-terminal proteolytic processing of alpha-N-acetyl-beta-endorphin(1-31) to form alpha-N-acetyl-beta-endorphin(1-27) and alpha-N-acetyl-beta-endorphin(1-26) also occurred when the labeled beta-endorphin-sized molecules were associated with the secretory granule fraction. The acetylation of alpha-melanocyte-stimulating hormone (alpha MSH)-sized molecules was also investigated in rat intermediate pituitary primary cell cultures by immunoprecipitation, gel filtration chromatography, and reverse-phase high pressure liquid chromatography. Pulse-chase labeling experiments showed that newly synthesized molecules co-migrating with adrenocorticotropic hormone ((ACTH)(1-13)NH2) were converted first to molecules similar to alpha MSH (alpha-N-acetyl-ACTH(1-13)NH2) and then to molecules similar to alpha-N,O-diacetyl-alpha MSH. These results demonstrate that the enzyme activity(s) responsible for the NH2-terminal acetylation of beta-endorphin alpha MSH-sized molecules is located in the secretory granules of the rat intermediate pituitary.},
	address = {United States},
	article-pii = {S0021-9258(18)34045-6},
	author = {Glembotski, C. C.},
	completed = {19821021},
	grantno = {etc.},
	history = {1982/09/10 00:00 [entrez]},
	issue = {17},
	journal = {The Journal of biological chemistry},
	keywords = {Acetylation, Animals, Chromatography, High Pressure Liquid, Chymotrypsin, Endorphins/isolation \& purification/*metabolism, Kinetics, Melanocyte-Stimulating Hormones/*metabolism, Microscopy, Electron, Peptide Fragments/analysis, Pituitary Gland/*metabolism, Rats, Subcellular Fractions/metabolism/ultrastructure, beta-Endorphin},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Sep},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {10493--500},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {EC 3.4.21.1 (Chymotrypsin)},
	revised = {20210210},
	source = {J Biol Chem. 1982 Sep 10;257(17):10493-500.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Acetylation of alpha-melanotropin and beta-endorphin in the rat intermediate pituitary. Subcellular localization.},
	title-abbreviation = {J Biol Chem},
	volume = {257},
	year = {1982}
}

@article{Glembotski_1981_JBiolChem_256_7433,
	abstract = {The subcellular localization of the post-translational processing steps which occur in the conversion of pro-adrenocorticotropic hormone (ACTH)/endorphin into beta-endorphin-sized molecules in rat intermediate pituitary has been studied. Primary cell cultures were incubated in radioactively labeled amino acids, and a subcellular fraction containing secretory granules was separated from a subcellular fraction containing rough endoplasmic reticulum and Golgi apparatus by centrifugation of homogenates on gradients on Percoll (Pharmacia Fine Chemicals). The radiolabeled beta-endorphin-related material in the granule and rough endoplasmic reticulum/Golgi apparatus fractions was quantitated by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis. A pulse-chase labeling experiment demonstrated that newly synthesized beta-endorphin-related material first appeared in the rough endoplasmic reticulum/Golgi apparatus fraction and after longer incubations (chase) appeared in the secretory granule fraction. After 2 h of chase incubation, about 85\% of the beta-endorphin-related material synthesized during the 30-min pulse incubation had been transferred from the rough endoplasmic reticulum/Golgi apparatus to the secretory granule fraction. The conversion of most of the newly synthesized pro-ACTH/endorphin into beta-lipotropin occurred in the rough endoplasmic reticulum/Golgi apparatus fraction, whereas the conversion of most of the beta-lipotropin into beta-endorphin-sized molecules occurred in the secretory granule fraction.},
	address = {United States},
	article-pii = {S0021-9258(19)68981-7},
	author = {Glembotski, C. C.},
	completed = {19810915},
	grantno = {AM-19859/AM/NIADDK NIH HHS/United States},
	history = {1981/07/25 00:00 [entrez]},
	issue = {14},
	journal = {The Journal of biological chemistry},
	keywords = {Adrenocorticotropic Hormone/*biosynthesis/*metabolism, Animals, Cells, Cultured, Endoplasmic Reticulum/metabolism, Endorphins/*biosynthesis/*metabolism, Golgi Apparatus/metabolism, Kinetics, Male, Pituitary Gland/*metabolism, Pro-Opiomelanocortin, Protein Biosynthesis, Protein Precursors/*metabolism, Rats, Subcellular Fractions/metabolism, Sulfur Radioisotopes},
	language = {eng},
	linking-issn = {0021-9258},
	month = {Jul},
	nlm-unique-id = {2985121R},
	owner = {NLM},
	pages = {7433--9},
	print-issn = {0021-9258},
	publication-status = {ppublish},
	registry-number = {9002-60-2 (Adrenocorticotropic Hormone)},
	revised = {20210210},
	source = {J Biol Chem. 1981 Jul 25;256(14):7433-9.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Subcellular fractionation studies on the post-translational processing of pro-adrenocorticotropic hormone/endorphin in rat intermediate pituitary.},
	title-abbreviation = {J Biol Chem},
	volume = {256},
	year = {1981}
}

@article{Glembotski_1981_JBacteriol_145_1374,
	abstract = {Escherichia coli strain CR341T28 will not grow at temperatures above 34 degrees C in liquid medium, and the adenylate kinase of this strain is heat sensitive. When a culture was shifted from a permissive (30 degrees C) to a nonpermissive (36 degrees C) temperature, the adenylate energy charge fell from 0.9 to 0.2, with a concurrent decrease in the number of viable cells and in the specific activity of adenylate kinase. When cultures of the temperature-sensitive strain were grown at temperatures above 30 degrees C, the adenylate energy charge, the specific activity of adenylate kinase, and the growth rate were lower than the corresponding parameters for the parental strain. By isotopic labeling of the adenine nucleotides in vivo, it was determined that increasing growth temperatures between 30 and 34 degrees C for the heat-sensitive strain resulted in a decrease in the adenosine triphosphate-to-adenosine monophosphate and adenosine triphosphate-to-adenosine diphosphate ratios. Between 26 and 30 degrees C the adenosine triphosphate-to-adenosine diphosphate ratio was essentially normal in the temperature-sensitive strain, but the adenosine triphosphate-to-adenosine diphosphate ratio was decreased. The adenylate ratios in the parental strain did not change between 30 and 34 degrees C. The adenylate kinase mass action ratio for each strain was essentially constant under all growth conditions. When assayed at 30 degrees C, the affinities of the enzyme from the mutant strain were somewhat lower than those of the parent adenylate kinase. The mutant enzyme also did not exhibit the substrate inhibition that was observed at high adenosine monophosphate concentrations with the parental enzyme. An increase in the assay temperature from 30 degrees to 40 degrees C had little or no effect on the Km values determined for the parental adenylate kinase, but caused the Km values determined for the mutant adenylate kinase to increase by a factor of two or more.},
	article-doi = {10.1128/jb.145.3.1374-1385.1981},
	author = {Glembotski, C. C. and Chapman, A. G. and Atkinson, D. E.},
	completed = {19810526},
	electronic-issn = {1098-5530},
	grantno = {GM-07185/GM/NIGMS NIH HHS/United States},
	history = {1981/03/01 00:00 [entrez]},
	issue = {3},
	journal = {Journal of bacteriology},
	keywords = {Adenosine Diphosphate/metabolism, Adenosine Monophosphate/*metabolism, Adenosine Triphosphate/metabolism, Adenylate Kinase/isolation \& purification/*metabolism, Escherichia coli/genetics/*metabolism, Hot Temperature, Kinetics, Mutation, Phosphotransferases/*metabolism},
	language = {eng},
	linking-issn = {0021-9193},
	month = {Mar},
	nlm-unique-id = {2985120R},
	owner = {NLM},
	pages = {1374--85},
	print-issn = {0021-9193},
	publication-status = {ppublish},
	registry-number = {EC 2.7.4.3 (Adenylate Kinase)},
	revised = {20210526},
	source = {J Bacteriol. 1981 Mar;145(3):1374-85. doi: 10.1128/jb.145.3.1374-1385.1981.},
	status = {MEDLINE},
	subset = {IM},
	timestamp = {2021.09.20},
	title = {Adenylate energy charge in Escherichia coli CR341T28 and properties of heat-sensitive adenylate kinase.},
	title-abbreviation = {J Bacteriol},
	volume = {145},
	year = {1981}
}