Inhibition of myosin IIA-actin interaction prevents ischemia/reperfusion induced cardiomyocytes apoptosis through modulating PINK1/Parkin pathway and mitochondrial fission
Inhibition of myosin IIA-actin interaction prevents ischemia/reperfusion induced cardiomyocytes apoptosis through modulating PINK1/Parkin pathway and mitochondrial fission
复制标题
抑制肌球蛋白 IIA-肌动蛋白相互作用通过调节 PINK1/Parkin 通路和线粒体裂变防止缺血/再灌注诱导的心肌细胞凋亡
DOI：
10.1016/j.ijcard.2018.04.079
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发表时间：
2018-11-15
影响因子：
3.5
通讯作者：
Yu, Boyang
中科院分区：
文献类型：
--
作者：
Li, Fang;Fan, Xiaoxue;Yu, Boyang
背景：线粒体分裂是心肌缺血/再灌注（MI/R）诱导心肌细胞凋亡的重要机制。肌球蛋白II由于在U2 OS细胞的分裂位点的募集和肌动球蛋白收缩而在分裂中起关键作用。然而，在调节MI/R诱导的心肌细胞线粒体分裂和凋亡的肌球蛋白IIA肌动蛋白的相互作用的作用仍有待于充分eluted.Methods和结果：当心肌细胞暴露于模拟I/R injury，肌球蛋白IIA蛋白从质膜易位到细胞质，与肌动蛋白丝相互作用，形成应力纤维和产生收缩力。用肌球蛋白II抑制剂blebbistatin治疗减弱了肌球蛋白IIA-肌动蛋白复合物诱导的肌动球蛋白收缩性，并防止心肌细胞凋亡，如通过抑制切割的caspase-3表达、Bcl-2/Bax水平正常化和凋亡细胞减少所反映的。同时，blebbistatin可抑制PINK 1/Parkin通路的激活，改善线粒体形态，抑制Drp 1在Ser 616位的磷酸化和易位，从而改善线粒体分裂。此外，肌球蛋白IIA的CRISPR/Cas9敲除阻断了I/R诱导的细胞凋亡，抑制了PINK 1/Parkin通路并减少了线粒体分裂。重要的是，在小鼠MI/R损伤模型中，blebbistatin减轻心肌细胞凋亡，抑制肌球蛋白IIA-肌动蛋白相互作用和PINK 1/Parkin通路，抑制心肌超微结构异常和线粒体分裂。抑制肌球蛋白IIA-肌动蛋白相互作用诱导的肌动球蛋白收缩性可以通过PINK 1/Parkin通路和线粒体分裂调节在体内外阻止心肌细胞凋亡和MI/R损伤，这可能适用于开发心血管疾病的治疗方法。(c)2018 Elsevier B. V.版权所有。
Background: Mitochondrial fission is the essential mechanisms of myocardial ischemia/reperfusion (MI/R)-induced cardiomyocytes apoptosis. Myosin II plays a key role in fission due to the recruitment and actomyosin constriction at the fission site in U2OS cells. However, the role of myosin IIA-actin interaction in regulating MI/R-induced cardiomyocytes mitochondrial fission and apoptosis remains to be fully elucidated.Methods and results: When cardiomyocytes are exposed to simulated I/R injury, the myosin IIA protein translocated from the juxtamembrane to the cytoplasm, interacted with actin filaments, formed stress fibers and generated contractile forces. Treatment with the myosin II inhibitor blebbistatin attenuated the myosin IIA-actin complex induced actomyosin contractility and prevented cardiomyocytes apoptosis as reflected by inhibition of cleaved caspase-3 expression, normalization of Bcl-2/Bax levels and decreased apoptotic cells. Meanwhile, blebbistatin inhibited the activation of PINK1/Parkin pathway and ameliorated mitochondrial fission as evidenced by improvement of mitochondrial morphology, inhibition of Drp1 phosphorylation at Ser616 and translocation. Furthermore, CRISPR/Cas9 knockout of myosin IIA blocked I/R-induced apoptosis, suppressed PINK1/Parkin pathway and reduced mitochondrial fission. Importantly, blebbistatin attenuated myocardial apoptosis, inhibited myosin IIA-actin interaction and PINK1/Parkin pathway, suppressed myocardial ultrastructure abnormalities and mitochondrial fission in a mouse MI/R injury model.Conclusions: Inhibition of actomyosin contractility induced by myosin IIA-actin interaction could impede myocardial apoptosis and MI/R injury via PINK1/Parkin pathway and mitochondrial fission modulation both in vitro and in vivo, which may be applicable for the development of therapies for cardiovascular diseases. (c) 2018 Elsevier B.V. All rights reserved.