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Menick Lab Image

Menick Research Lab

Donald R. Menick, Ph.D.Donald R. Menick, Ph.D.

Professor
Research Faculty
Director, Gazes Cardiac Research Institute
Division of Cardiology

 

My laboratory is focused on the analysis of signaling and gene regulatory pathways, which play a role in cardiac failure. Recently, we have demonstrated that protein acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a significant role in modulating gene expression in cardiac pathologies. Importantly, treatment with HDAC inhibitors preserves ventricular remodeling and cardiac function in pre-clinical models of cardiac hypertrophy, myocardial infarction (MI), ischemia reperfusion (IR) and heart failure. We have determined that HDAC inhibitors promote the polarization of inflammatory M1 macrophages to anti-inflammatory M2 macrophages, resulting in reduced deleterious remodeling and preserve cardiac function in the post MI heart. Our study is the first account of the benefit of HDAC inhibition being due in part to its ability to polarize macrophages, a cellular component underappreciated until recently in cardiac pathologies. Our work has also identified a mechanism that has served as a paradigm of how HDACs can mediate both repression and activation of gene expression. We have also identified an important mechanism whereby HDAC inhibitors can repress cardiac gene expression by altering the acetylation state of co-activator and co-repressors of transcription. We have also shown that the acetylation state of specific transcription factors affects their interaction with co-activators and co-repressors. Therefore, HDACs can facilitate gene activation via the direct deacetylation of transcription factors allowing for recruitment of co-activators to the promoter. Our overall goal is to translate our basic and pre-clinical discoveries into important new therapies for patients with heart disease.