Abstract 175: Pro-survival Function of Mef2 in Cardiomyocytes is Enhanced by β-blockers
β1-adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes via activation of cAMP/ protein kinase A (PKA) signaling. β-adrenergic receptor antagonists, or β-blockers, oppose the action of PKA signaling by blocking the β1-receptor and effectively inhibit apoptosis and heart failure. The Myocyte Enhancer Factor 2 (MEF2) proteins have been implicated as nuclear targets for signaling cascades involved in muscle-gene expression and have important roles in proliferation, apoptosis and survival in multiple cell types. We previously reported that PKA signaling represses MEF2 activity. Here, we assessed whether β-blockers can inhibit neonatal cardiac myocyte apoptosis by interfering with PKA dependent MEF2 repression. We show that siRNA mediated MEF2 loss of function induced cardiomyocyte apoptosis. β1AR activation by isoproterenol treatment represses MEF2 transcriptional activity and promotes apoptosis in neonatal cardiomyocytes and, importantly, this effect was reversed in cells expressing a PKA resistant form of MEF2D (S121/190A), as indicated by FACS analysis. We also report that a β-blocker, Atenolol, antagonizes isoproterenol induced apoptosis and also acutely enhanced MEF2 transcriptional activity. We observed that β-adrenergic stimulation modulated MEF2 cellular localization in neonatal cardiomyocytes and this was reversed by atenolol treatment. In addition, we also document that Kru[[Unable to Display Character: ̈]]ppel-like factor 6 (KLF6) is an important MEF2 target gene and loss of function analysis using siRNA-mediated knockdown of KLF6 expression resulted in cardiomyocyte apoptosis. Collectively, these observations, establish that MEF2 plays an important pro-survival role in cardiomyocytes which can be modulated by β-adrenergic signaling. These observations have important clinical implications and may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology.
Author Disclosures: S. Hashemi: None. J. Salma: None. S. Wales: None. J.C. McDermott: None.
- © 2015 by American Heart Association, Inc.