Numerous studies have demonstrated the occurrence of myocyte apoptosis during myocardial infarction, ischemia-reperfusion injury, and heart failure. Despite these observations, the two most critical questions in the field remain poorly understood: 1. What is the precise mechanism of apoptosis in cardiac myocytes? 2. To what extent does myocyte apoptosis contribute to the changes in myocardial structure and function that characterize these disease states? The research program described herein addresses both of these interrelated questions in the case of chronic heart failure. The applicant's laboratory has previously demonstrated that the signals that elicit cardiac myocyte apoptosis in complex pathophysiologic states are, not unexpectedly, transduced via multiple pathways, inhibition of any one of which is insufficient to abrogate apoptosis. In contrast, the caspases, a novel family of cysteine proteases, constitute the final common pathway for apoptosis in all metazoan cells from worm to mammal. Indeed the applicant's preliminary data show that blockade of caspase activation markedly inhibits cardiac myocyte apoptosis in vivo. The significance of this result is that caspase inhibition provides a means to determine the contribution of myocyte apoptosis to the pathogenesis of heart failure. Accordingly, the objective of this application is to delineate the roles of caspase activation and myocyte apoptosis in heart failure. This objective will be accomplished through the following specific aims: 1. To determine which of the caspases are activated in cardiac myocytes by pro-apoptotic component stimuli of heart failure and whether caspase activation is necessary for these stimuli to kill cardiac myocytes. 2. To determine the effect of inhibiting myocyte apoptosis on cardiac structure and function during experimental heart failure in vivo. 3. To determine the sufficiency of caspase activation to induce cardiomyopathy in vivo. Taken together, this research program will define the role of caspase activation in cardiac myocyte apoptosis and the role of cardiac myocyte apoptosis itself in the pathogenesis of chronic heart failure. In so doing, these studies may provide the conceptual framework for novel heart failure therapies based on apoptosis inhibition.
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