Mitochondrial Src tyrosine kinase plays a role in the cardioprotective effect of ischemic preconditioning by modulating complex I activity and mitochondrial ROS generation
Mitochondrial Src tyrosine kinase plays a role in the cardioprotective effect of ischemic preconditioning by modulating complex I activity and mitochondrial ROS generation
复制标题
线粒体 Src 酪氨酸激酶通过调节复合物 I 活性和线粒体 ROS 生成在缺血预处理的心脏保护作用中发挥作用
DOI：
10.3109/10715762.2015.1050013
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发表时间：
2015-01-01
影响因子：
3.3
通讯作者：
Xu, Z.
中科院分区：
文献类型：
--
作者：
Ge, H.;Zhao, M.;Xu, Z.
摘要虽然缺血预处理（IPC）和其他心脏保护干预措施已被提出，以保护心脏免受缺血/再灌注（I/R）损伤，通过抑制线粒体复合物I的活性在再灌注后，复杂的I活动的确切机制的调制仍然是难以捉摸的。本研究旨在验证IPC通过激活线粒体Src酪氨酸激酶来调节再灌注时复合物I活性，并诱导心肌保护作用的假设。离体大鼠心脏预处理3个周期的5分钟缺血和5分钟再灌注前30分钟指数缺血，然后2小时的再灌注。线粒体Src磷酸化（Tyr 416）在I/R期间显著降低，这意味着I/R使Src酪氨酸激酶失活。IPC增加线粒体Src磷酸化再灌注后，这是抑制选择性Src酪氨酸激酶抑制剂PP 2。选择性Src酪氨酸激酶抑制剂PP 2可抑制IPC的抗梗死作用。复合物I活性显着增加再灌注后，IPC的Src酪氨酸激酶依赖性的方式防止的效果。作为支持，在复合物I中发现Src和磷酸化Src。此外，IPC防止缺氧/复氧诱导的大鼠心肌细胞线粒体活性氧（ROS）的产生和细胞损伤，这是由PP 2撤销。最后，IPC减少由缺氧/复氧和模拟缺血/再灌注诱导的LDH释放，这种作用被PP 2和Src siRNA逆转。这些数据表明，线粒体Src酪氨酸激酶占IPC对复合物I和线粒体ROS生成的抑制作用，从而发挥了作用，在IPC的心脏保护作用。
Abstract While ischemic preconditioning (IPC) and other cardioprotective interventions have been proposed to protect the heart from ischemia/reperfusion (I/R) injury by inhibiting mitochondrial complex I activity upon reperfusion, the exact mechanism underlying the modulation of complex I activity remains elusive. This study was aimed to test the hypothesis that IPC modulates complex I activity at reperfusion by activating mitochondrial Src tyrosine kinase, and induces cardioprotection against I/R injury. Isolated rat hearts were preconditioned by three cycles of 5-min ischemia and 5-min reperfusion prior to 30-min index ischemia followed by 2 h of reperfusion. Mitochondrial Src phosphorylation (Tyr416) was dramatically decreased during I/R, implying inactivation of Src tyrosine kinase by I/R. IPC increased mitochondrial Src phosphorylation upon reperfusion and this was inhibited by the selective Src tyrosine kinase inhibitor PP2. IPC's anti-infarct effect was inhibited by the selective Src tyrosine kinase inhibitor PP2. Complex I activity was significantly increased upon reperfusion, an effect that was prevented by IPC in a Src tyrosine kinase-dependent manner. In support, Src and phospho-Src were found in complex I. Furthermore, IPC prevented hypoxia/reoxygenation-induced mitochondrial reactive oxygen species (ROS) generation and cellular injury in rat cardiomyocytes, which was revoked by PP2. Finally, IPC reduced LDH release induced by both hypoxia/reoxygenation and simulated ischemia/reperfusion, an effect that was reversed by PP2 and Src siRNA. These data suggest that mitochondrial Src tyrosine kinase accounts for the inhibitory action of IPC on complex I and mitochondrial ROS generation, and thereby plays a role in the cardioprotective effect of IPC.