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. ? ?
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