UCP2 protect the heart from myocardial ischemia/reperfusion injury via induction of mitochondrial autophagy
UCP2 protect the heart from myocardial ischemia/reperfusion injury via induction of mitochondrial autophagy
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UCP2通过诱导线粒体自噬保护心脏免受心肌缺血/再灌注损伤
DOI：
10.1002/jcb.28812
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发表时间：
2019-09-01
影响因子：
4
通讯作者：
Yang, Jun
中科院分区：
文献类型：
--
作者：
Wu, Hui;Ye, Ming;Yang, Jun
解偶联蛋白2（Uncoupling protein 2，UCP 2）是UCP的主要亚型，位于线粒体内膜，在人和啮齿类动物的心脏等组织中均有表达。然而，其在心肌缺血/再灌注（I/R）过程中的功能作用尚未完全了解。缺血预处理（IPC）可显著改善缺血后心肌功能恢复，减少乳酸脱氢酶（LDH）释放，同时上调UCP 2。然后，我们研究了UCP 2在IPC中的作用，通过腺病毒介导的体内UCP 2过表达（AdUCP 2）和敲低（AdshUCP 2）对心肌I/R损伤的心脏保护作用。IPC诱导的保护作用被UCP 2过表达所模仿，而UCP 2沉默则被取消。从机制上讲，UCP 2过表达显著增强了I/R诱导的线粒体自噬（mitophagy），如线粒体自噬的生化标志所测量的。此外，感染AdUCP 2的原代心肌细胞增加了模拟缺血/再灌注（sI/R）诱导的线粒体自噬，因此逆转了受损的线粒体功能。最后，在培养的心肌细胞中用mdivi-1抑制线粒体自噬，消除了UCP 2-对sI/R诱导的线粒体功能障碍和细胞死亡提供了保护作用。我们的数据确定了UCP 2通过加强线粒体自噬防止线粒体功能障碍来对抗心肌I/R损伤的关键作用。我们的研究结果揭示了UCP 2在心肌I/R过程中的心脏保护作用的新机制。
Uncoupling protein 2 (UCP2), located in the mitochondrial inner membrane, is a predominant isoform of UCP that expressed in the heart and other tissues of human and rodent tissues. Nevertheless, its functional role during myocardial ischemia/reperfusion (I/R) is not entirely understood. Ischemic preconditioning (IPC) remarkably improved postischemic functional recovery followed by reduced lactate dehydrogenase (LDH) release with simultaneous upregulation of UCP2 in perfused myocardium. We then investigated the role of UCP2 in IPC-afforded cardioprotective effects on myocardial I/R injury with adenovirus-mediated in vivo UCP2 overexpression (AdUCP2) and knockdown (AdshUCP2). IPC-induced protective effects were mimicked by UCP2 overexpression, while which were abolished with silencing UCP2. Mechanistically, UCP2 overexpression significantly reinforced I/R-induced mitochondrial autophagy (mitophagy), as measured by biochemical hallmarks of mitochondrial autophagy. Moreover, primary cardiomyocytes infected with AdUCP2 increased simulated ischemia/reperfusion (sI/R)-induced mitophagy and therefore reversed impaired mitochondrial function. Finally, suppression of mitophagy with mdivi-1 in cultured cardiomyocytes abolished UCP2-afforded protective effect on sI/R-induced mitochondrial dysfunction and cell death. Our data identify a critical role for UCP2 against myocardial I/R injury through preventing the mitochondrial dysfunction through reinforcing mitophagy. Our findings reveal novel mechanisms of UCP2 in the cardioprotective effects during myocardial I/R.