Heart failure is the end-stage condition of a number of cardiac disorders. Cardiac hypertrophy is the main risk factor for heart failure, peroxisome proliferator activated receptors (PPARalpha, -delta and -gamma), plays important roles in regulating lipid metabolic genes. Our laboratory has previously based on studies on a unique cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta-/-) mouse line demonstrated that the PPARdelta subtype as a determinant of basal myocardial fatty acid oxidation (FAO). These studies established that PPARdelta is an essential determinant of myocardial FAO. Recent studies suggest that synthetic ligands of PPARdelta exert anti-hypertrophic effects on cultured cardiomyocytes. Our preliminary studies indicated that PPARdelta expression is downregulated in hypertrophied ventricles. In addition, PPARdelta activation and overexpression in cultured cardiomyocytes suppressed inflammatory response in cultured cardiomyocytes. However, it remains unclear whether PPARdelta exerts anti-hypertrophic effects in response to hypertrophic stimuli. In this proposed project we will utilize the cultured cardiomyocyte system and the conditional cardiomyocyte-specific mouse models to test the central hypothesis that PPARdelta is a key regulator of cardiac growth in response to hypertrophic stimuli via crosstalks with other transcriptional pathways that are involved in cardiac growth. We will specifically study the following aims: to determine if PPARdelta interferes with other signaling pathways to influence cell growth of cultured cardiomyocytes in vitro;to determine the role of PPARdelta in the development of cardiac hypertrophy in vivo;and to determine the role of PPARdelta in the progression from compensated remodeling to heart failure. Results from these studies should provide in vivo evidence on a potential role of PPARdelta as a negative regulator of cardiac hypertrophic growth and progression to heart failure. Further understanding the molecular mechanisms underlying the development of cardiac hypertrophy and heart failure should help to provide novel therapeutic targets to treat heart failure.
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