Targeting MEF2 acetylation improves myocardial recovery and overall survival in mice

Abstract

Abstract Background Post-myocardial infarct remodeling is a complex process that is strongly associated with the eventual development of heart failure, and involves myocyte hypertrophy, specific alterations in gene expression and mitochondrial metabolism, myocyte death, fibrosis, and incursion of inflammatory mediators. Many of these alterations involve dynamic changes in lysine acetylation (KAc), a key regulatory post-transcriptional modification in the nucleus and cytosol, and can be blocked by small molecules with broad activity against histone deacetylases (HDACi). The downstream targets of HDACi and other KAc modulators remain to be established, and the safety of this class of agent for long-term administration in heart failure is similarly unknown. We recently reported that a small molecule probe (8MI) selectively blocking acetylation of transcription factor MEF2 is effective in preventing and reversing pressure overload hypertrophy in vivo, without altering overall histone acetylation. Hypothesis Treatment with a MEF2-selective KAc modulator will accelerate cardiac functional recovery after myocardial infarction. Methods The left coronary artery was permanently ligated (PCO) in 8–10 week C57BL/6J mice; controls underwent thoracotomy only (Sham). Within each group, half received 8MI (20–100mg/kg) by gavage daily, beginning at 30 min, and half received diluent only (DMSO). Treatment was continued for 31 days with weekly echocardiography. Mice from each group (n=3–6) were euthanized weekly for gross and histological analysis. Separately, mice were subjected to transverse aortic banding (TAC) +/− 8MI. Comparative LV RNASeq data were analysed using Gene Set Enrichment Analysis at 4 weeks, and median survival was determined. Results At 24 hours all PCO vs. Sham mice had reduced ejection fraction (62.1±1.08% vs. 80.9±1.08%), increased LV diastolic dimensions, and decreased systolic wall thickening (n =min. 8 per group, p < E-001). Over 4 weeks, heart weights progressively increased in PCO mice together with lung and liver congestion. 8MI dose-dependently improvedeach of these parameters, with near-normal function and organ weights at 4 weeks in higher-dose groups. 8MI also reduced infarct size, compensatory hypertrophy, and fibrosis at 4 weeks. In parallel, 8MI extended median survival by 1.67-fold after TAC (127.5 vs 76 days, p<0.0001, 8MI vs DMSO). RNASeq +GSEA analysis revealed that 8MI treatment blocked MEF2 target gene induction, while enriching for gene sets Oxidative Phosphorylation and Myc Targets (FDR q values 0.000 and 0.041) compared with DMSO. Conclusion An inhibitor of MEF2 acetylation promoted significant functional and pathological recovery in a mouse model of myocardial infarction, associated with suppression of MEF2-dependent transcription. These findings point to a novel approach to preventing myocardial functional decline, and improving survival, after myocardial injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health; Miami Heart Research Institute