Abstract 14681: MicroRNA-20a Inhibits Stress-induced Cardiomyocyte Apoptosis
Increased biomechanical stress is a potent inductor of cardiomyocyte apoptosis, which in turn contributes to maladaptive remodeling. Despite substantial progress in the understanding of the molecular pathophysiology, many components of the signaling pathways underlying remodeling in general and apoptosis in particular still remain unknown. Recent evidence suggests that microRNAs (miRs) play an important role in the ability of the heart to respond to increased cardiac stress. To identify novel modulators of cardiac remodeling, we conducted a genome-wide miR-screen of mechanically stretched neonatal rat cardiomyocytes (NRCM). Out of 351 miRs, six were significantly regulated by biomechanical stress, including miR-20a, which is part of the miR17∼92 cluster. Interestingly, further expression analyses revealed that miR-20a showed a biphasic regulation in models of cardiac remodeling (MI, pressure overload) with an initial upregulation and subsequent downregulation under chronic stress. Since we identified miR-20a in an in vitro model of cardiomyocyte hypertrophy, we first asked whether miR-20a modulates the hypertrophic response. We thus generated an adenovirus encoding miR-20a which allowed for overexpression in cardiomyocytes. Yet, neither at baseline conditions nor after phenylephrine (PE)-treatment, overexpression of miR-20a (50 ifu) led to a differential change in cell size. Given the potential apoptosis-modulating properties of the miR17∼92 cluster, we next subjected NRCM to a hypoxia/”reperfusion” model. Interestingly, AdmiR-20a significantly inhibited hypoxia-mediated apoptosis in a dose-dependent fashion. Conversely, targeted knockdown of miR-20a via transfection of NRCM with a specific anti-miR significantly induced cardiomyocyte apoptosis. Mechanistically, the antiapoptotic effect of miR-20a appears to be mediated through targeting and subsequent downregulation of the proapoptotic transcription factor E2F1. Taken together, MiR-20a is upregulated in models of acute cardiac stress and attenuates hypoxia-induced apoptosis in cardiomyocytes. These properties reveal miR-20a as a cardioprotective miR and a potential target for novel therapeutical strategies to prevent pathological cardiac remodeling.
- © 2010 by American Heart Association, Inc.