Unfolded protein response signaling in myocardial response to ischemia

Cardiovascular diseases, including myocardial infarction and heart failure, are the leading cause of death worldwide. Although acute myocardial infarction survival rates have increased, the damage to the myocardium remains largely irreversible and heart failure mortality has increased over the previous several decades. New therapeutic techniques are necessary to address the issue of irreversible damage to the myocardium after acute injury and the increasing mortality due to heart failure. The unfolded protein response (UPR) has been implicated in numerous cardiovascular diseases including myocardial infarction and ventricular remodeling during heart failure. However, the importance of specific UPR components in cardiovascular disease has not been evaluated. It is not clear how UPR signaling via its adaptive, defensive and apoptotic components determines the fate of the myocardium during disease. Accordingly, the overall hypothesis of this dissertation is that UPR signaling is essential to the myocardial response to ischemia by promoting cardioprotective pathways and attenuating detrimental stress-induced signaling pathways. The studies presented in this dissertation show that: 1). The endogenous, cardioprotection elicited by brief cycles of ischemia and reperfusion prior to myocardial infarction, termed ischemic preconditioning (PC), activate the unfolded protein response and that induction of activating transcription factor (ATF3) by endoplasmic reticulum (ER) stress is essential for the cardioprotective effects of ischemic PC. 2). During ventricular remodeling after myocardial infarction, ATF3 is robustly induced and activated to negatively regulate myocardial fibrosis possibly by inhibition of atrial natriuretic peptide (ANP) transcription.;The results of these studies support the overall hypothesis that UPR signaling is a critical component of the myocardial response to ischemia and regulates stress-induced signaling pathways. Data presented here demonstrate the UPR signaling component ATF3 is a novel, necessary component of the cardioprotective pathways that diminish irreversible damage to the myocardium due to ischemic injury and demonstrate a role for ATF3 in regulating the fibrotic response during the progression from myocardial infarction to heart failure.