Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy

摘要

Unknown molecular responses to sarcomere protein gene muta-tions account for pathologic remodeling in hypertrophic cardiomy-opathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC~(403/+)) and an Mef2-dependent p-galactosidase reporter transgene. In young, prehyper-trophic MHC~(403/+) mice the reporter was not activated. In hypertro-phic hearts, activation of the Mef2-dependent reporter was re-markably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC~(403/+) myocytes with Mef2-dependent reporter activation reexpressed the fetal my-osin isoform (βMHC), a molecular marker of hypertrophy, although MHO~(403/+) myocytes with or without PMHC expression were compa-rably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC~(403/403) mice, which have acceler-ated remodeling, widespread myocyte necrosis, and neonatal lethal-ity. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC~(403/403) hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2-dependent reporter ac-tivity before death. Our data dissociate myocyte hypertrophy, a con-sistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial re-lationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC~(403/+) and MHC~(403/403) hearts defines Mef2 activa-tion as a molecular signature of stressed HCM myocytes that are poised to die.