Cardiac hypertrophy is the main risk factor for congestive heart failure, which is the end-stage condition of a number of cardiac disorders. Deregulation of redox homeostasis in the heart has been implicated in the development of cardiac hypertrophy and heart failure. Recent studies suggest that PPARgamma may exert anti-hypertrophic effects with unknown mechanism(s). Our preliminary studies revealed that mice with - cardiomyocyte-restricted PPARgamma deficiency showed substantially increased superoxide in their heart prior to progressive cardiac hypertrophy and progression to heart failure. We postulate that PPARgamma is an essential determinant of myocardial redox homeostasis via transcriptional regulation of a key endogenous mitochondrial antioxidant, magenese, superoxide dismutase (SOD2), in the heart, thus serving as a pivotal regulator for the heart in response to various pathophysiological conditions. We will use a combination of in vitro, in vivo and ex vivo methods to test our central hypothesis that cardiac PPARgamma improves pathological left ventricular hypertrophic responses in cardiomyocytes by activating expression of SOD2 to diminish harmful superoxide in cardiomyocytes. Specifically, we will achieve the following specific aims:
aim 1, to determine how PPARgamma regulates expression of genes encoding SOD2 in vitro;
aim 2, to determine effects of cardiac PPARgamma on SOD2 expression in mice with either cardiomyocyte-restricted knockout of PPARgamma or overexpression of a constitutively active PPARgamma;
aim 3, to define the role of PPARgamma in the progression from compensated cardiac hypertrophy to heart failure using a targeted inducible cardiomyocyte-restricted PPARgamma knockout mice. We will also determine if SOD2 mimetic drugs ameliorates or prevents further oxidative damage in the cardiomyocyte-restricted PPARgamma knockout mice. We will characterize PPARgamma controlled antioxidant gene expression, cardiac morphology, reactive oxygen species production, cardiac function, myocardial bioenergetics and oxidative damage in the heart of PPARgamma transgenic mice during the development of cardiac hypertrophy and heart failure induced by pressure-overload. Results from these studies should provide novel mechanisms on the regulation of cardiac redox homeostasis and hence provide new insights into novel therapeutic targets for the prevention and treatment of cardiac hypertrophy and heart failure. ? ? ?
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