Caveolins and Heart Failure

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PROJECT SUMMARY (See instructions): Heart failure remains a major public health problem and effective therapies are limited. Recent work by our group and others has suggested that caveolins, structured proteins involved in numerous cell functions including cell growth and hypertrophy may be novel targets for heart failure therapy. Work in our laboratory has shown that the muscle specific subtype of caveolin, Caveolin-3 (Cav-3) is a critical molecule in protecting the myocardium from myocardial stress. In addition, we have shown recently that cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) produces increased survival and enhanced cardiac function in the transverse aortic constriction (TAC) model of heart failure. The precise mechanisms involved in the attenuation of heart failure by Cav-3 remain to be elucidated and are the focus of the current unit. Caveolae are a specialized subset of lipid rafts enriched in cholesterol, sphingolipids and caveolins. Caveolae and caveolins are now known to produce critical interactions between the sarcolemmal membrane and cytoplasmic organelles including mitochondria in cardiac myocytes. Mitochondrial dysfunction is a critical element of heart failure progression. Caveolins have been found in mitochondrial membranes, however the role of caveolins and their effects on mitochondrial function have not been investigated. We have developed exciting novel preliminary data that show 1) an intimate relationship between caveolae and mitochondria that is increased by myocardial stress, 2) the presence of Cav-3 within the inner mitochondrial membrane of mitochondria, 3) the overexpression of Cav-3 in cardiac myocytes increases Cav-3 within mitochondria and improves mitochondrial function, and 4) targeting Cav-3 specifically to mitochondria produces improved mitochondrial function and reduced oxidative stress in cardiac myocj1:es. Based on these compelling preliminary data we will test the hypothesis that Cav-3 can alter the progression of heart failure via modulation of mitochondrial function. We will use state of the art molecular biology, imaging technology, electron paramagnetic resonance technology and physiological techniques in cardiac myocytes and clinically relevant models of heart failure to focus on mechanism and produce important preclinical data to support the potential use of caveolins as novel therapeutics for heart failure patients.