Agradecimentos: We thank the Brazilian Biosciences National Laboratory (LNBio) at Brazilian Centre for Research in Energy and Materials (CNPEM), for financial support and access to all facilities: Viral Vector Laboratory (LVV), The Biological Imaging Facility (LBI), Laboratory of Spectroscopy and Calorimetry (LEC) and DNA microarray facility (LMA). We thank Model Organism Laboratory (LOM) at LNBio/CNPEM for generating the transgenic mice and providing animal facility. This work was funded by São Paulo Research Foundation (FAPESP; Grants 2008/53519 - 5, 2008/53583 - 5) and Brazilian National Research Council (CNPq; Grants 304366/2009-9, 312203/2012-8 and 310536/2014-6). The funding agencies had no involvement in the design, performance, or analysis of the study Ver menos

Abstract: 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 a, ß and ? provides transcript diversity with gene activation or repression functionalities. Neonatal and adult rat ventricular myocytes were used to overexpress MEF2C splicing variants ?+ (repressor) or ?-, or the inactive MEF2C?+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?+ or MEF2C?- 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?+ in failing hearts. We demonstrate a previously unrealized upregulation of the transrepressor MEF2C?+ isoform in human and mouse failing hearts. We show that adenovirus-mediated overexpression of MEF2C?+ 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?-. Transgenic mice overexpressing MEF2C?+, but not the MEF2C?-, developed dilated cardiomyopathy, correlated to cell-cycle reentry and apoptosis of cardiomyocytes. Our results provide a mechanistic link between MEF2C?+ and deleterious abnormalities in cardiomyocytes, supporting the notion that splicing dysregulation in MEF2C towards the selection of the MEF2C?+ variant contributes to the pathogenesis of HF by promoting cardiomyocyte dropout Ver menos