Regulation of Cardiac Signaling by Class I Histone Deacetylases

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DESCRIPTION (provided by applicant): The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of heart failure. With greater than five million heart failure patients in the U.S. alone, treatment of this conditio represents an estimated annual cost to the American health care system of over $37 billion. The 5-year mortality rate following first admission for heart failure is 42.3%, highlighting an urgent need for new therapeutic approaches. HDACs catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 HDACs are encoded by distinct genes. Broad-spectrum, 'pan'-HDAC inhibitors are efficacious in rodent models of heart failure, blocking pathological cardiac hypertrophy and fibrosis and improving cardiac function, suggesting an application for HDAC inhibitors for the treatment of human heart failure. However, since pan-HDAC inhibition is associated with toxicities such as thrombocytopenia, the potential for translating these findings to the heart failure clinic remains unclear. The current proposal is based on the overall hypothesis that class I HDACs contribute to the pathogenesis of heart failure by altering MAP kinase signaling in cardiac myocytes. As an extension of this hypothesis, we propose that selective inhibition of class I HDACs with small molecule inhibitors will provide a safe and effective therapeutic strategy for heart failure. Our preliminary data indicate that class I HDACs alter nuclear ERK1/2 signaling in cardiomyocytes by inducing expression of an ERK-specific phosphatase, DUSP5. Further studies will define the mechanisms for regulation of DUSP5 by class I HDACs, and the role of DUSP5 in the control of cardiac remodeling in vitro and in vivo. In vivo evaluation will include echocardiographic and catheter-based measurements of cardiac function as well as histological and morphometric assessment of cardiac hypertrophy and fibrosis. Together, results from these in vitro and in vivo studies will provide insights into signaling and transcriptional events controlling heart failure, and should provide the foundation for innovative approaches to drug discovery for heart failure based on isoform-selective HDAC inhibition.