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

Autor:	Pereira AHM; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Cardoso AC; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Consonni SR; Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil., Oliveira RR; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Saito A; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Vaggione MLB; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Matos-Souza JR; Department of Internal Medicine, University of Campinas, Campinas, Brazil., Carazzolle MF; Genomics and Expression Laboratory, University of Campinas, Campinas, Brazil., Gonçalves A; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil., Fernandes JL; Jose Michel Kalaf Research Institute, Campinas, Brazil., Ribeiro GCA; Cardiovascular Surgery, Pontifical Catholic University, Campinas, Brazil., Lopes MM; Cardiology, Pontifical Catholic University, Campinas, Brazil., Molkentin JD; Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USA., Franchini KG; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), 13083-970 Campinas, Sao Paulo, Brazil; Department of Internal Medicine, University of Campinas, Campinas, Brazil. Electronic address: kleber.franchini@lnbio.cnpem.br.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2020 Jan; Vol. 51, pp. 102571. Date of Electronic Publication: 2020 Jan 03.
DOI:	10.1016/j.ebiom.2019.11.032
Abstrakt:	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 α, β and γ provides transcript diversity with gene activation or repression functionalities. Methods: 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. Findings: 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. Interpretation: 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. Funding: São Paulo Research Foundation (FAPESP); Brazilian National Research Council (CNPq). Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest. (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu