Our long-term objectives are to understand signaling pathways that protect the heart from stress-induced damage. Such pathways often foster hypertrophic myocardial cell growth, which can eventually lead to impaired cardiac function and heart failure. However, the ER stress response (ERSR), which is activated by stresses that alter protein folding in the RER (e.g. hypoxia), fosters cell survival but not cell growth. One pro-survival branch of the ERSR is mediated by the ER membrane protein, ATF6 alpha. Upon ER stress, 90 kDa (p90) ATF6 alpha is cleaved by regulated intramembranous proteolysis (RIP), the p50 cleavage product becomes a transcription factor that induces ER stress response genes (ERSRGs). ERSRGs encode proteins that resolve the ER stress, promote cell survival, but do not induce cell growth. We have shown that in cardiac myocytes, SR/ER Ca ATPase-2 (SERCA2) is induced in an ER stress- and ATF6 alpha-dependent manner. Thus, in addition to protecting the myocardium from stress by inducing numerous pro-survival genes, via ATF6-mediated SERCA2 induction, the ERSR may also foster preservation of myocardial contractility. The recent discovery of a second form of ATF6, ATF6 beta, and our preliminary results that ATF6 beta inhibits ATF6 alpha-mediated ERSRG induction, support our hypothesis that ATF6 alpha and beta possess opposing properties that provide the basis of a novel mechanism for fine-tuning ERSRG induction and optimal cardiac protection.
Specific Aims : To address this hypothesis the Specific Aims we propose are to: 1) characterize the rates of generation and degradation of the p50 forms of ATF6 alpha and beta in cultured cardiac myocytes exposed to ER stress, 2) map the domains of p50 ATF6 alpha and beta that regulate ERSRG induction and ATF6 degradation, and 3) co-express native or mutated p50 ATF6 beta with native p50 ATF6 alpha in various alpha/beta ratios, and assess the effects on SERCA2 induction, Ca transients, cell growth and survival of cultured cardiac myocytes. The ERSR has gone virtually unstudied in the heart; accordingly, the proposed studies are novel and will enhance our understanding of the ERSR and the roles played by ATF6 alpha and beta in the stressed myocardium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS025037-17
Application #
6728093
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Porter, John D
Project Start
1986-12-01
Project End
2008-02-29
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
17
Fiscal Year
2004
Total Cost
$349,188
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Glembotski, Christopher C (2014) Roles for ATF6 and the sarco/endoplasmic reticulum protein quality control system in the heart. J Mol Cell Cardiol 71:11-5
Meex, Steven J R; Weissglas-Volkov, Daphna; van der Kallen, Carla J H et al. (2009) The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels. Arterioscler Thromb Vasc Biol 29:1322-7
Glembotski, Christopher C (2008) The role of the unfolded protein response in the heart. J Mol Cell Cardiol 44:453-9
Glembotski, Christopher C (2007) Getting a G--RRP on regulated exocytosis in the heart. J Cell Biol 179:371-3
Thuerauf, Donna J; Marcinko, Marie; Belmont, Peter J et al. (2007) Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. J Biol Chem 282:22865-78
Martindale, Joshua J; Fernandez, Rayne; Thuerauf, Donna et al. (2006) Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res 98:1186-93
Kato, Takahiro; Muraski, John; Chen, Yan et al. (2005) Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt. J Clin Invest 115:2716-30
Martindale, Joshua J; Wall, Jason A; Martinez-Longoria, Diana M et al. (2005) 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. J Biol Chem 280:669-76
Thuerauf, Donna J; Morrison, Lisa; Glembotski, Christopher C (2004) Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem 279:21078-84
Morrison, Lisa E; Whittaker, Ross J; Klepper, Robert E et al. (2004) Roles for alphaB-crystallin and HSPB2 in protecting the myocardium from ischemia-reperfusion-induced damage in a KO mouse model. Am J Physiol Heart Circ Physiol 286:H847-55

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