Abstract 15206: Small Molecules Targeting the MEF2: Coactivator Interface Block Cardiac Hypertrophy and Normalize Cardiac Function Following Pressure Overload
Background: Cardiac hypertrophy is associated with progressive cardiac dysfunction, and is an independent risk factor for death. Myocyte enhancer factor 2 (MEF2) is comprised of 4 closely homologous transcription factors that are tonically silenced by interaction with class II histone deacetylases and acetylated by p300 acetyltransferase during hypertrophy. Recent structural analyses have revealed a common interaction site on MEF2 for both HDACs and p300.
Hypothesis: Structure-based small molecules that occupy the co-regulatory site on MEF2 will significantly attenuate the hypertrophic response to pressure overload.
Methods: Crystallographic models and mammalian expression systems were used in conjunction with a ZINC library of small molecules to identify compounds with the potential to bind the hydrophobic groove on the shared MADS-box/MEF2 domain of all MEF2 isoforms. Select candidate small molecules were assessed in neonatal rat ventricular myocyte (NRVM) and transverse aortic coarctation (TAC) models of murine cardiac hypertrophy. RT-PCR, immunohistochemistry, echocardiography, and serum biomarkers were used to evaluate the molecular and functional impact of these compounds.
Results: We synthesized a family of molecules that disrupted the interaction between MEF2 and HDAC4 in vitro; members of this group were found to blunt serum-induced hypertrophy and ANP expression of NRVM in a dose-dependent manner (p< 0.01 for both). The most potent of these (MEF2I-8MI) was then delivered by weekly IV injection to mice before and after TAC. Compared with vehicle (DMSO), 8MI-injected animals exhibited dose-dependent normalization of myocardial mass and myocyte size, despite comparable workload. Histology demonstrated reduced fibrosis and myocyte apoptosis with increasing doses of 8MI. Remarkably, TAC-induced left ventricular dysfunction was also reversed with 8MI dose escalation, associated with reduced ANP expression (EF 50% without 8MI vs. 75% with 8MI 40μg/g, p <0.005). No evidence of systemic toxicity was seen.
Conclusions: Small molecules targeting MEF2 function in vivo demonstrate the nodal position of MEF2 in mediating maladaptive hypertrophy, and show that inhibition of hypertrophy can be achieved, preserving cardiac function.
- © 2013 by American Heart Association, Inc.