Abstract 19425: A Small Molecule Enforcing MEF2 Deacetylation Prevents and Reverses Hypertrophy and Normalizes Cardiac Function in Multiple Stress Models

Abstract

Background: Cardiac hypertrophy leads to progressive cardiac dysfunction, and is an independent risk factor for death. Myocyte enhancer factor 2 (MEF2) is silenced by interaction with class IIa histone deacetylases and activated by p300 acetyltransferase during hypertrophy. Hypothesis: Targeting the co-regulatory site on MEF2 will prevent and reverse hypertrophy and associated cardiac dysfunction. Methods: Transverse aortic coarctation (TAC) and swimming stress models were used to initiate cardiac hypertrophy in male C57Bl/6 mice. Mice swam for 3 hours twice daily; control mice were immersed briefly. 8MI was administered by daily IP injection at a dose of 40 mg/kg beginning either at the time of intervention (TAC, swimming stress) or 4 weeks afterward (TAC) and continued for 4 weeks. N ≥ 5 per group. RT-PCR, immunohistochemistry, and echocardiography were used to assess cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were treated with 8MI, the histone deacetylase inhibitors MC1568 (class IIa-selective) or trichostatin A (nonselective, TSA). Results: Both TAC and forced swimming induced pathological hypertrophy with deterioration in systolic function in mice receiving DMSO (p<0.001 for both). 4 weeks after TAC or the initiation of swimming, 8MI-treated animals had myocardial mass and function similar to those of sham-operated or immersed-control mice. After 8MI treatment was stopped at 4 weeks, hypertrophy developed in mice that continued to swim, similar to DMSO-treated animals. In mice with established hypertrophy 4 weeks after TAC, treatment with 8MI, but not DMSO, reversed systolic dysfunction (n=5 per group, p=0.0018) and reduced myocardial wall thickness to near that of sham-operated animals. No evidence of systemic toxicity was seen. Mechanistically, 8MI, but not MC1568, promoted HDAC4 nuclear retention and maintained MEF2 in a deacetylated state, and unlike TSA, prevented EP300 accumulation. Conclusions: Pharmacological targeting of MEF acetylation in vivo prevents and reverses stress-associated hypertrophy in multiple models. Reversal of hypertrophy by this means improves systolic function and does not prevent successful adaptation to increased cardiac work.