Role of dual-specificity phosphatase 5 (DUSP5) in the regulation of right ventric

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DESCRIPTION (provided by applicant): Heart failure is a major cause of disease and death in the US and worldwide. Features of this disease are heart enlargement (hypertrophy) and heart stiffness (fibrosis), which result in impaired heart contraction and relaxation. The five-year deat rate following first admission of heart failure is >40%, stressing the need for new therapeutic strategies. Histone deacetylase (HDAC) inhibitors have emerged as a new class of drugs that have been shown as effective in reducing cardiac hypertrophy and ultimately improving heart failure in pre- clinical models. We previously published that HDAC inhibition blocks nuclear ERK1/2 signaling, and thus hypertrophy, by upregulating the nuclear ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5) in cardiac myocytes. However, nothing is known about the in vivo function of DUSP5 in the heart. Recent studies demonstrate that nuclear ERK1/2 signaling is a central regulator of pathological cardiac hypertrophy in animal models of HF. In preliminary studies, we postulated that DUSP5 null mice would develop exaggerated cardiac hypertrophy in response to stress due to enhanced nuclear ERK phosphorylation. Indeed, DUSP5-deficient mice had significantly larger left ventricles (LVs), as well as enhanced ERK1/2 activation, compared to wild- type littermates in response to treatment with the ¿-adrenergic agonist, isoproterenol (ISO). Curiously, ISO did not induce RV hypertrophy in wild-type mice, but triggered a ~40% increase in RV mass in DUSP5 null mice. These data suggest a prominent role for DUSP5 in the control of RV hypertrophy. Significantly, relative to LV hypertrophy, little is known about the molecular mechanisms controlling pathological RV growth. This application will fill a critical void by testing the hypothesis that DUSP5 functions as a signl-dependent repressor of cardiac hypertrophy by dephosphorylating nuclear ERK1/2, and this mechanism is especially critical for suppression of RV hypertrophy. To test our hypothesis, we have developed two specific aims. Aim 1 will elucidate the mechanism(s) by which HDACs control DUSP5 expression in cardiac myocytes using chromatin immunoprecipitation (ChIP) and DNA methylation techniques to determine epigenetic regulatory events within the dusp5 promoter. In Aim 2, we will address the in vivo role ofDUSP5 in the control of nuclear ERK1/2 phosphorylation and pathological RV hypertrophy in animal models of heart failure. The proposed study will significantly add to our limited knowledge regarding RV growth, potentially facilitating development of better therapies for patients with right-sided heart failure.