Our long-term objectives are to understand signaling pathways that mediate cardiac protection during stress. Many protective pathways studied to date foster myocardial cell growth. Although initially adaptive, this growth leads to tissue remodeling and, eventually, to impaired cardiac function. Accordingly, it would be desirable to identify protective pathways that do not induce cell growth; one such pathway may be the unfolded protein response (UPR). The UPR, which has been virtually unstudied in the cardiac context, is activated by stresses that alter the folding of proteins made in the rough ER. Ischemia/reperfusion (I/R), a well known cardiac stress, activates certain aspects of the UPR in the brain. In model systems, such as HeLa and 3T3 cells, one branch of the UPR, mediated by the recently discovered transcription factor, ATF6, induces genes that promote cell survival (i.e. ER stress response [ERSR] genes), but does not activate cell growth. Protective roles for ATF6 have not been studied in any tissue to date. Our hypothesis is that I/R activates the UPR in isolated cardiac myocytes and in the heart, and that subsequent stimulation of the ATF6 branch of the UPR fosters ERSR gene induction and cardioprotection without hypertrophic growth. To address this hypothesis the Specific Aims are to: ? 1) characterize ATF6 activation and ERSR gene induction in cultured cardiac myocytes and in isolated hearts by simulated and global I/R, respectively, ? 2) use novel ligand-regulated forms of ATF6 (LR-ATF6) to examine the effects of ATF6 activation on ERSR gene induction, hypertrophic growth and survival in cultured cardiac myocytes during simulated I/R, and ? 3) assess the ability of ATF6 to mediate ERSR gene induction and cardioprotection in vivo, using transgenic mice featuring cardiac-restricted expression of LR-ATF6. These studies will provide a better understanding of the UPR in the heart, which is required to grasp the importance of this pathway and ATF6 in preserving contractile function in the stressed myocardium. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075573-02
Application #
6836539
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
2003-12-17
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$339,750
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
Arrieta, A; Blackwood, E A; Glembotski, C C (2018) ER Protein Quality Control and the Unfolded Protein Response in the Heart. Curr Top Microbiol Immunol 414:193-213
Glembotski, Christopher C (2017) Expanding the Paracrine Hypothesis of Stem Cell-Mediated Repair in the Heart: When the Unconventional Becomes Conventional. Circ Res 120:772-774
Gray, Charles B B; Suetomi, Takeshi; Xiang, Sunny et al. (2017) CaMKII? subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-?B and TNF-?. J Mol Cell Cardiol 103:48-55
Jin, Jung-Kang; Blackwood, Erik A; Azizi, Khalid et al. (2017) ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circ Res 120:862-875
Reynolds, Julia O; Quick, Ann P; Wang, Qiongling et al. (2016) Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release. Int J Cardiol 225:371-380
Doroudgar, Shirin; Quijada, Pearl; Konstandin, Mathias et al. (2016) S100A4 protects the myocardium against ischemic stress. J Mol Cell Cardiol 100:54-63
Glembotski, Christopher C (2015) Breaking down the COP9 Signalsome in the heart: how inactivating a protein ubiquitin ligase increases protein ubiquitylation and protects the heart. Circ Res 117:914-6
Doroudgar, Shirin; Völkers, Mirko; Thuerauf, Donna J et al. (2015) Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes. Circ Res 117:536-46
Völkers, Mirko; Doroudgar, Shirin; Nguyen, Nathalie et al. (2014) PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med 6:57-65
Glembotski, Christopher C (2014) Finding the missing link between the unfolded protein response and O-GlcNAcylation in the heart. Circ Res 115:546-8

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