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.
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