MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure

Background: A pathophysiological link exists between dysregulation of MEF2C transcription factors and heart failure (HF), but the underlying mechanisms remain elusive. Alternative splicing of MEF2C exons alpha, beta and and gamma provides transcript diversity with gene activation or repression functionalities. Methods: Neonatal and adult rat ventricular myocytes were used to overexpress MEF2C splicing variants gamma+ (repressor) or gamma-, or the inactive MEF2C gamma+23/24 (K23T/R24L). Phenotypic alterations in cardiomyocytes were determined by confocal and electron microscopy, flow cytometry and DNA microarray. We used transgenic mice with cardiac-specific overexpression of MEF2C gamma+ or MEF2C gamma-to explore the impact of MEF2C variants in cardiac phenotype. Samples of non-infarcted areas of the left ventricle from patients and mouse model of myocardial infarction were used to detect the expression of MEF2C gamma+ in failing hearts. Findings: We demonstrate a previously unrealized upregulation of the transrepressor MEF2C gamma+ isoform in human and mouse failing hearts. We show that adenovirus-mediated overexpression of MEF2C gamma+ downregulates multiple MEF2-target genes, and drives incomplete cell-cycle reentry, partial dedifferentiation and apoptosis in the neonatal and adult rat. None of these changes was observed in cardiomyocytes overexpressing MEF2C gamma-. Transgenic mice overexpressing MEF2C gamma+, but not the MEF2C gamma-, developed dilated cardiomyopathy, correlated to cell-cycle reentry and apoptosis of cardiomyocytes. Interpretation: Our results provide a mechanistic link between MEF2C gamma+ and deleterious abnormalities in cardiomyocytes, supporting the notion that splicing dysregulation in MEF2C towards the selection of the MEF2C gamma+ variant contributes to the pathogenesis of HF by promoting cardiomyocyte dropout. (C) 2019 The Authors. Published by Elsevier B.V.