Heart failure is a significant cause of morbidity and mortality in the US. Little is known about the molecular regulatory events involved in the development of cardiac hypertrophy or during the transition to heart failure. During cardiac hypertrophy, the chief myocardial energy substrate switches from fatty acids to glucose; a reversion of fetal energy metabolism. The clinical manifestations of human inborn errors in cardiac fatty oxidation (FAO) enzymes, including hypertrophic cardiomyopathy and heart failure suggest that reduced capacity for myocardial fatty acid utilization leads to hypertrophic cardiac growth and ultimately to reduced ventricular function. Recently, we have shown that the transcription of genes encoding FAO enzymes is repressed in hypertrophied heart via two groups of transcription factors; Sp proteins and the orphan nuclear receptor COUP-TF. This proposal is designed to test the hypothesis that the gene regulatory pathway involved in the repression of FAO enzyme expression during the development of cardiac hypertrophy involves re-induction of fetal transcriptional control and is an integral component of the cardiac growth program. In addition, we hypothesize that the energy substrate switch known to occur during cardiac hypertrophy becomes maladaptive and, thus, promotes development of heart failure. The specific goals of this proposal include; i) characterization of the cis-acting DNA regulatory elements and corresponding transcription factors involved in the repression of genes encoding enzymes involved in two pivotal steps in the FAO pathway using several established cardiac myocyte in vitro hypertrophy systems and an in vivo ventricular pressure overload preparation in transgenic mice (Specific Aims 1, 2), ii) delineation of proximal (upstream) regulatory events responsible for the activation of COUP-TF and Sp proteins during cardiac hypertrophic growth including studies to determine whether COUP- TF is phosphorylated via mitogen activated kinases (Specific Aim 3); and iii) overexpression of the transcription factors in transgenic mice to determine whether activation of this pathway triggers cardiac hypertrophy in vivo and promotes the transition to cardiac failure (Specific Aim 4). The phenotypic characterization of the transgenic mice will include examination of target gene expression, gross and histologic studies of myocyte structure, and in vivo analyses using echocardiography and cardiac MRI. The long-term objective of this project is to develop experimental and, ultimately, therapeutic strategies aimed at the potentially maladaptive energy substrate switches known to occur during development of heart failure.
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