Cardiac myocytes die by apoptosis in a variety of pathophysiological conditions including ischemiareperfusion and heart failure. Over the past 5 years, a body of work from the Pl's lab and others has demonstrated that inhibition of this cell death through genetic or pharmacologic means decreases myocardial damage, limits left ventricular remodeling, 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 and a potential therapeutic target. Little is known, however, about 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. ARC markedly inhibits cardiac myocyte apoptosis elicited by diverse stimuli. Preliminary studies from the Prs lab demonstrate that ARC potently antagonizes both the death receptor and mitochondrial death pathways through direct interactions with key components of those pathways (Fas, FADD, procaspase-8, and Bax). Thus, ARC appears to be a master-repressor of apoptosis in striated muscle. We propose to elucidate ARC's molecular mechanisms of action and to define its biological importance for cardiac myocyte survival in vivo:
Aim 1. To delineate the molecular mechanisms by which ARC inhibits the death receptor and mitochondrial pathways.
Aim 2. To determine whether ARC is critical for cardiac myocyte survival under basal and stressed conditions in vivo using conditional knockout mice.
Aim 3. To determine whether forced maintanence of ARC levels using inducible transgenic mice ameliorates left ventricular remodeling and dysfunction induced by hemodynamic overload.
These aims constitute a highly integrated program that examines the most critical aspects of ARC from the single molecule to the intact animal. The resulting information will advance our understanding of ARC's molecular mechanisms and biological roles in the myocardium. Moreover, this information may provide the basis for novel and specific heart failure therapies based on modulating the abundance and interactions of ARC. ? ?
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