Cardiac Myocyte Apoptosis: Mechanism and Significance

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Cardiac myocytes die by apoptosis during ischemia-reperfusion injury and heart failure. A body of work from the Pl's lab and others has demonstrated that inhibition of this cell death through pharmacologic or genetic means decreases myocardial damage, limits left ventricular dilation, improves contractile function, and in some cases, decreases mortality. These studies provide the initial "proof of concept" that cardiac myocyte apoptosis is an important pathogenic mechanism for ischemia-reperfusion injury and heart failure and suggest that inhibition of cell death may provide a novel therapeutic target for these disorders. We now wish to focus our attention on the molecular regulation of apoptosis specifically in cardiac myocytes. The central death machinery has been highly conserved from worm to human and differs little among various cell types. Despite this, apoptosis is often regulated in a cell type- and stimulus-specific manner, the basis of which is poorly understood. ARC (Apoptosis Repressor with a CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that is expressed primarily in cardiac and skeletal muscle. It is the only cardiac-enriched apoptosis regulatory molecule identified to date. ARC's importance is underscored by its potent inhibition of cardiac myocyte apoptosis elicited by diverse stimuli. Little is known, however, about ARC's mechanism of action, regulation, and in vivo effects. We will begin to define these areas through the following aims: 1. To determine the mechanism of ARC's novel interactions with and regulation of the apoptotic DNA degradation machinery. 2. To determine the mechanism of ARC degradation during apoptosis. 3. To determine whether persistent myocardial expression of ARC in vivo attenuates acute and chronic abnormalities in cardiac structure and function due to ischemia-reperfusion injury. Taken together, these studies will deepen our mechanistic and physiological understanding of ARC. This information may provide the basis for strategies to exploit this cardiac-enriched endogenous inhibitor to design novel and specific therapies for ischemic heart disease and heart failure.