Role of CHF1/Hey2 in Hypertrophy and Heart Failure

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DESCRIPTION (provided by applicant): Cardiac hypertrophy is 'both a physiologic process allowing for adaptation to hemodynamic load and a pathologic process ultimately resulting in chamber dilatation and progression to heart failure. Heart failure is a leading cause of morbidity and mortality in Western Society, with the incidence increasing every year. Although multiple signaling pathways have been implicated in the development of hypertrophy, the molecular mechanisms that regulate the transition from a normal, physiologic response to a maladaptive, pathological response are poorly understood. In addition, the molecular mechanisms responsible for the progression from hypertrophy to heart failure remain to be elucidated. Finally, factors that negatively regulate hypertrophy are even less well characterized, and are of tremendous interest due to their potential therapeutic value. We have previously cloned the basic helix-loop-helix, hairy-related transcriptional repressor, CHF1/Hey2, and determined that mice lacking this transcription factor develop a dilated cardiomyopathy. We have also found that transgenic mice overexpressing CHF1/Hey2 in the myocardium are resistant to phenylephrine-induced hypertrophy. Furthermore, we have found that CHF1/Hey2 interacts with GATA4, a known activator of hypertrophy, and suppresses GATA4-dependent transcription. Our findings suggest that CHF1/Hey2 is an important regulator of hypertrophy and heart failure. To elucidate the mechanisms by which CHF/Hey2 regulates the development of hypertrophy and the progression to heart failure, we propose the following specific aims: Aim 1: Determine the effects of CHF1/Hey2 on GATA4-dependent transcriptional mechanisms associated with hypertrophy Aim 2: Determine how CHF1/Hey2 affects hypertrophic transcriptional pathways through time series analysis of gene expression Aim 3: Generate CHF1/Hey2 conditional knockout mice lacking CHF1/Hey2 in the myocardium and measure their response to hypertrophy in vivo