Abstract 4839: Colocalization of Regional MEF2 Activity With Myocardial Scarring in Hypertrophic Cardiomyopathy

Abstract

Background- The molecular triggers activated by a sarcomere gene mutation that remodel the heart and produce histopathologic manifestations of hypertrophic cardiomyopathy (HCM) are incompletely known. Myocyte enhancer factor 2 (MEF2) has emerged as a critical regulator of gene expression in the heart. Objective- To examine whether MEF2 is essential for HCM pathogenesis, we assessed in vivo MEF2 expression versus myocyte hypertrophy, disarray and interstitial fibrosis, the prototypic histopathology of HCM. Methods and Results- Wild-type or heterozygous mice harboring an Arg403Gln missense mutation in the alpha-myosin heavy chain gene (MHC403/+ mice) were crossed with transgenic mice harboring a MEF2-dependent reporter gene. Mouse hearts at 30 weeks of the age were evaluated by beta-galactosidase staining to detect transcriptional activity of MEF2 in vivo. Activity of MEF2 was heterogeneously increased in the left ventricle of MHC403/+ mouse hearts compared with wild-type mouse hearts. Gomori’s trichrome staining for collagen revealed that regional activation of MEF2 uniquely colocalized with myocardial scarring in MHC403/+ mouse hearts whereas only baseline activity of MEF2 was detected in the area without myocardial scarring. von Kossa staining revealed myocardial necrosis near to MEF2 staining. To further explore whether MEF2 activity is involved in the pathogenesis of myocardial necrosis, mice carrying a homozygous Arg403Gln mutation (MHC403/403) and the MEF2-dependent reporter gene were analyzed. MEF2 was regionally activated in 3-days old MHC403/403 mouse hearts, in advance of the myocardial necrosis that occurs in homozygous mutant hearts. At 6-days, greater MEF2 activity was observed compared with 3-days old MHC403/403 hearts, and massive necrosis was present where MEF2 was activated. Conclusions- These findings provide the first evidence for regional activation of the MEF2-pathway is involved in evolution of myocardial fibrosis and necrosis in HCM. Because myocyte loss and myocardial scarring is implicated in the progression of ventricular dysfunction, these data indicate that strategies to prevent MEF2 activation may attenuate remodeling and heart failure development.