Mdivi-1 alleviates cardiac fibrosis post myocardial infarction at infarcted border zone, possibly via inhibition of Drp1-Activated mitochondrial fission and oxidative stress
Mdivi-1 alleviates cardiac fibrosis post myocardial infarction at infarcted border zone, possibly via inhibition of Drp1-Activated mitochondrial fission and oxidative stress
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DOI：
10.1016/j.abb.2022.109147
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发表时间：
2022-02-12
影响因子：
3.9
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
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作者：
Ding, Jie;Zhang, Zhihao;Wang, Dao Wen
线粒体分裂抑制剂1（Mdivi-1）已被证明在多种疾病中发挥有益作用，主要通过抑制drp1介导的线粒体裂变。Mdivi-1对梗死边界区心肌纤维化的影响及其可能的机制尚不清楚。本研究旨在探讨Mdivi1对心肌梗死后反应性心肌纤维化和心功能的影响及其可能机制。小鼠随机分为6组（每组n = 9）： Sham；Mdivi-1;心肌梗死7 d;MI 14 d;MI 28 d;MI 28d + Mdivi-1。采用LAD冠状动脉结扎法制造心肌梗死模型。Mdivi-1 （1 mg/kg）从第2天开始，每隔一天给药一次，直至小鼠牺牲（共14次注射Mdivi-1）。体外实验，在NIH3T3细胞中检测Mdivi-1对tgf - β 1诱导成纤维细胞纤维化相关病理生理变化的影响。我们发现Mdivi-1显著减弱心肌梗死后梗死边界区成纤维细胞活化、胶原生成和纤维化，改善受损的心功能。在机制上，我们观察到Mdivi-1降低了梗死边缘区心肌成纤维细胞P-Drp1-S616的蛋白表达和线粒体分裂异常。此外，我们发现Mdivi-1的作用部分依赖于增加Hmox1的表达和抑制氧化应激。综上所述，Mdivi-1可通过减弱drp1介导的线粒体裂变，减轻梗死边界区心肌纤维化，部分改善心功能受损。此外，抑制氧化应激可能是Mdivi-1的另一个潜在作用机制，这可能是由于Hmox1的上调。
Mitochondrial division inhibitor 1(Mdivi-1) has been shown to play a beneficial role in a variety of diseases, mainly by inhibiting Drp1-mediated mitochondrial fission. The effects of Mdivi-1 on cardiac fibrosis at infarcted border zone area and its possible mechanism remain unclear. This study aimed to investigate the effects of Mdivi1 on reactive cardiac fibrosis and cardiac function post myocardial infarction and its potential mechanisms. Mice were randomly divided into six groups (n = 9 for each group): Sham; Mdivi-1; MI 7d; MI 14d; MI 28d; MI 28d + Mdivi-1. The MI model was induced by ligation of LAD coronary artery. Mdivi-1 (1 mg/kg) was administered to mice every other day at a time from the second day until the sacrifice of the mice (total 14 injection of Mdivi-1). In vitro experiments, the effect of Mdivi-1 on TGF-beta 1-induced fibrosis-related pathophysiological changes of fibroblasts was examined in NIH3T3 cells. We found that Mdivi-1 significantly attenuated fibroblast activation, collagen production and fibrosis at infarcted border zone after MI, improved impaired heart function. Mechanistically, we observed that Mdivi-1 reduced the protein expression of P-Drp1-S616 and abnormal mitochondrial fission of cardiac fibroblasts in the infarcted border zone area. In addition, we found that the effects of Mdivi-1 partially relied on increasing the expression of Hmox1 and inhibiting oxidative stress. In conclusion, Mdivi-1 could attenuate cardiac fibrosis at infarcted border zone and improve impaired heart function partially through attenuation of Drp1-mediated mitochondrial fission. Moreover, inhibition of oxidative stress, which is possible due to the up-regulation of Hmox1, may be another potential mechanism of action of Mdivi-1.