NDUFA4L2 protects against ischaemia/reperfusion-induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I
NDUFA4L2 protects against ischaemia/reperfusion-induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I
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DOI：
10.1111/1440-1681.12768
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发表时间：
2017-07-01
影响因子：
2.9
通讯作者：
Long, Jingning
中科院分区：
文献类型：
--
作者：
Li, Jianhua;Bai, Caiyan;Long, Jingning
心肌缺血/再灌注(I/R)损伤可导致心肌细胞凋亡和线粒体功能障碍。本研究旨在探讨NADH脱氢酶1α亚单位4样亚单位2(NDUFA4L2)对心肌缺血再灌注(I/R)损伤的影响及其分子机制。用H9c2细胞模拟缺血再灌注损伤，建立体外缺氧再灌注模型。用RT-PCR和Western印迹检测NDUFA4L2和Complex I的表达水平。流式细胞仪检测H9c2细胞的凋亡率，免疫印迹法检测Bax和Bcl2的表达。线粒体功能以ATP浓度、MPTP开放和细胞色素C(Cyto C)表达为指标。我们的数据表明，NDUFA4L2在心肌H/R损伤中的表达显著下调。NDUFA4L2过表达可显著抑制缺氧/复氧诱导的细胞凋亡，同时下调Bax的表达，上调Bcl2的表达。同时，NDUFA4L2的增强显著地阻止了缺氧/再灌注引起的线粒体功能障碍，这体现在ATP浓度的增加，MPTP开放的延迟，以及Cyto C表达的下调。此外，NDUFA4L2对复合体I的激活有上调和负向调节作用。沉默复合体I明显减轻细胞凋亡和线粒体功能障碍。综上所述，我们的研究结果表明，NDUFA4L2通过复合体I预防心肌细胞凋亡和线粒体功能障碍，从而保护心肌细胞免受H/R损伤，可能是一种潜在的减轻心肌I/R损伤的治疗方法。
Myocardial ischaemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as mitochondrial dysfunction. The aims of the present study were to investigate whether NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) on myocardial ischaemia-reperfusion (I/R) injury and the underlying molecular mechanism. The hypoxia-reperfusion (H/R) model was established in vitro using H9c2 cells to simulate I/R injury. NDUFA4L2 and complex I expression levels were detected using RT-PCR and western blot. The apoptosis of H9c2 cells was evaluated by flow cytometry and the expression of Bax and Bcl-2 was detected by western blot. The mitochondrial function was assessed by ATP concentration, mPTP opening and cytochrome c (cyto C) expression. Our data indicated that NDUFA4L2 expression was significantly down-regulated in myocardial H/R injury. Overexpression of NDUFA4L2 led to a dramatic prevention of H/R-induced apoptosis accompanied by a decrease in the expression of Bax and an increase in the expression of Bcl-2. Meanwhile, augmentation of NDUFA4L2 dramatically prevented mitochondrial dysfunction caused by H/R as reflecting in the increased ATP concentration, delayed mPTP opening, as well as down-regulated cyto C expression. Moreover, complex I activation was heightened and negatively regulated by NDUFA4L2. Silencing complex I conspicuously attenuated cell apoptosis and mitochondrial dysfunction. Taken together, our findings demonstrated that NDUFA4L2 protects against H/R injury by preventing myocardium apoptosis and mitochondrial dysfunction via the complex I, and may be a potential therapeutic approach for attenuating myocardial I/R injury.