Cardiac hypertrophy is a common condition often predisposing to heart failure and sudden death. Despite recent progress in the identification of cellular signaling pathways involved in cardiac hypertrophic growth, little is known about the downstream molecular events that lead to contractile dysfunction in the hypertrophied heart. The expression of enzymes involved in mitochondrial fatty acid oxidation (FAO), the chief cardiac energy source, is coordinately downregulated in acquired forms of pathologic cardiac hypertrophy. We have recently demonstrated that this metabolic regulatory switch is due to deactivation of a transcriptional regulatory complex comprised of the nuclear receptor, PPARalpha, and its cardiac-enriched, coactivator PGC- 1. This renewal proposal is designed to test the hypothesis that the activity of PPARalpha/PGC-l plays a critical role in determining whether the hypertrophied heart becomes dysfunctional (pathologic remodeling) or maintains normal function as with physiologic forms of hypertrophy. We propose that the activity of PPARalpha is influenced by a balance of upstream signaling pathways linked to growth stimuli. The experiments planned for Specific Aim 1 are designed to characterize the upstream signaling events controlling the activity of the PPARalpha/PGC-1 complex and its target genes involved in mitochondrial metabolism during hypertrophic growth. The goal of Specific Aim 2 will be to evaluate the regulation of this energy metabolic pathway during physiologic hypertrophic growth due to exercise training. The objective of Specific Aim 3 is to systematically evaluate the effects of PPARalpha and PGC-1 in pathologic forms of cardiac hypertrophy using gain-of-function and loss-of-function genetic strategies in mice. The cardiac phenotype of these mice will be evaluated using molecular biologic, physiologic, and metabolic endpoints. Experiments proposed in Specific Aim 4 will evaluate the cardiac metabolic and functional response of mice lacking PPARalpha or PGC- 1 to exercise training. The longterm objective of this project is to identify molecular targets for novel therapeutic strategies aimed at preventing the pathologic metabolic remodeling of the hypertrophied heart.
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