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

EBioMedicine 2020 Jan

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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 α, β and γ provides transcript diversity with gene activation or repression functionalities. Neonatal and adult rat ventricular myocytes were used to overexpress MEF2C splicing variants γ+ (repressor) or γ-, or the inactive MEF2Cγ+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 MEF2Cγ+ or MEF2Cγ- 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 MEF2Cγ+ in failing hearts. We demonstrate a previously unrealized upregulation of the transrepressor MEF2Cγ+ isoform in human and mouse failing hearts. We show that adenovirus-mediated overexpression of MEF2Cγ+ 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 MEF2Cγ-. Transgenic mice overexpressing MEF2Cγ+, but not the MEF2Cγ-, developed dilated cardiomyopathy, correlated to cell-cycle reentry and apoptosis of cardiomyocytes. Our results provide a mechanistic link between MEF2Cγ+ and deleterious abnormalities in cardiomyocytes, supporting the notion that splicing dysregulation in MEF2C towards the selection of the MEF2Cγ+ variant contributes to the pathogenesis of HF by promoting cardiomyocyte dropout. São Paulo Research Foundation (FAPESP); Brazilian National Research Council (CNPq). Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Ana Helena M Pereira, Alisson C Cardoso, Silvio R Consonni, Renata R Oliveira, Angela Saito, Maria Luisa B Vaggione, Jose R Matos-Souza, Marcelo F Carazzolle, Anderson Gonçalves, Juliano L Fernandes, Gustavo C A Ribeiro, Mauricio M Lopes, Jeffery D Molkentin, Kleber G Franchini. MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure. EBioMedicine. 2020 Jan;51:102571