Cardioprotective effects of α-cardiac actin on oxidative stress in a dilated cardiomyopathy mouse model
Cardioprotective effects of α-cardiac actin on oxidative stress in a dilated cardiomyopathy mouse model
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DOI：
10.1096/fj.201902389r
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发表时间：
2019-12-29
期刊：
影响因子：
4.8
通讯作者：
Decaux, Jean-Francois
中科院分区：
文献类型：
--
作者：
Angelini, Aude;Gorey, Mark-Alexander;Decaux, Jean-Francois
α-心脏肌动蛋白的表达，心肌细胞的细胞骨架的主要组成部分，显着减少在扩张型心肌病小鼠模型引发的诱导型心脏特异性血清反应因子（Srf）基因破坏，可以模仿某些形式的人类扩张型心肌病。为了研究在该模型中α-心脏肌动蛋白表达维持的后果，我们开发了一种新的基于Cre/LoxP策略的转基因小鼠，其允许同时诱导SRF损失和α-心脏肌动蛋白的补偿性表达。在这里，我们报告说，心肌细胞内α-心脏肌动蛋白的维持通过对结构和转录水平的积极影响，暂时保护了细胞结构免受不利的心脏重塑。这些保护作用在体内伴随着ROS生成和蛋白质羰基化的减少以及NADPH氧化酶NOX 2和NOX 4的下调。我们还表明，异位表达的α-心脏肌动蛋白保护HEK 293细胞对过氧化氢诱导的氧化应激。氧化应激在心脏重构的发展中起重要作用，也参与心力衰竭的发病机制。总之，这些发现表明，α-心脏肌动蛋白可能参与氧化应激的调节，这是扩张型心肌病发展过程中不良重塑的主要原因。
The expression of alpha-cardiac actin, a major constituent of the cytoskeleton of cardiomyocytes, is dramatically decreased in a mouse model of dilated cardiomyopathy triggered by inducible cardiac-specific serum response factor (Srf) gene disruption that could mimic some forms of human dilated cardiomyopathy. To investigate the consequences of the maintenance of alpha-cardiac actin expression in this model, we developed a new transgenic mouse based on Cre/LoxP strategy, allowing together the induction of SRF loss and a compensatory expression of alpha-cardiac actin. Here, we report that maintenance of alpha-cardiac actin within cardiomyocytes temporally preserved cytoarchitecture from adverse cardiac remodeling through a positive impact on both structural and transcriptional levels. These protective effects were accompanied in vivo by the decrease of ROS generation and protein carbonylation and the downregulation of NADPH oxidases NOX2 and NOX4. We also show that ectopic expression of alpha-cardiac actin protects HEK293 cells against oxidative stress induced by H2O2. Oxidative stress plays an important role in the development of cardiac remodeling and contributes also to the pathogenesis of heart failure. Taken together, these findings indicate that alpha-cardiac actin could be involved in the regulation of oxidative stress that is a leading cause of adverse remodeling during dilated cardiomyopathy development.