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).

中文翻译：

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MEF2C阻遏物变体失调导致细胞周期重新进入并导致心力衰竭。

背景技术MEF2C转录因子失调与心力衰竭（HF）之间存在病理生理联系，但潜在的机制仍然难以捉摸。MEF2C外显子α，β和γ的可变剪接提供了具有基因激活或抑制功能的转录本多样性。方法使用新生和成年大鼠心室肌细胞过表达MEF2C剪接变体γ+（阻遏物）或γ-，或失活的MEF2Cγ+ 23/24（K23T / R24L）。通过共聚焦和电子显微镜，流式细胞术和DNA微阵列测定心肌细胞的表型改变。我们使用具有心脏特异性MEF2Cγ+或MEF2Cγ-过表达的转基因小鼠来研究MEF2C变体对心脏表型的影响。使用来自患者的左心室非梗塞区域和心肌梗塞的小鼠模型的样本来检测MEF2Cγ+在衰竭心脏中的表达。结果我们证明了在人和小鼠衰竭心脏中反式抑制因子MEF2Cγ+亚型的先前未实现的上调。我们显示，腺病毒介导的MEF2Cγ+的过表达下调了多个MEF2目标基因，并在新生和成年大鼠中驱动不完全的细胞周期折返，部分去分化和凋亡。在过表达MEF2Cγ-的心肌细胞中未观察到这些变化。过表达MEF2Cγ+而不是MEF2Cγ-的转基因小鼠发展为扩张型心肌病，与心肌细胞的细胞周期再进入和凋亡相关。解释我们的结果提供了MEF2Cγ+与心肌细胞有害异常之间的机制联系，支持了以下观点：MEF2C的剪接失调对MEF2Cγ+变体的选择有助于促进心肌细胞的脱落，从而导致HF的发病机理。基金会圣保罗研究基金会（FAPESP）；巴西国家研究委员会（CNPq）。