PPAR-delta in Cardiac Hypertrophy and Heart Failure

Morehouse School Of Medicine, Atlanta GA

Investigators

Linked publications & trials

Abstract

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