Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation
Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation
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DOI：
10.1152/ajpheart.00552.2001
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发表时间：
2002-02-01
影响因子：
4.8
通讯作者：
Terzic, A
中科院分区：
文献类型：
--
作者：
Ozcan, C;Bienengraeber, M;Terzic, A
钾通道开放剂具有保护线粒体免受缺氧损伤的作用。然而，在氧化应激下负责线粒体保护的机制尚未完全了解。在这里，线粒体从大鼠心脏中分离出来，并进行20分钟的缺氧，然后再复氧。在复氧时，活性氧（ROS）的产生增加与ADP刺激的耗氧量减少，ATP产生减弱，线粒体结构完整性破坏，细胞色素c释放相关。原型K+通道开放剂二氮嗪显着减少线粒体ROS生产在复氧与29 μ M的半最大效果。二氮嗪还保存氧化磷酸化和线粒体膜的完整性，如电子显微镜所示，并减少细胞色素c的释放。二氮嗪的保护作用由结构独特的K+通道开放剂尼可地尔重现，并由5-羟基癸酸（一种短链脂肪酸衍生物和线粒体ATP敏感性K+通道的假定阻断剂）拮抗。超氧化物歧化酶和过氧化氢酶组成的自由基清除剂系统模拟开放剂介导的线粒体保护作用。然而，开放剂对ROS产生的影响保持在名义上的K+-无介质中的存在或不存在的K+离子载体缬氨霉素，并模仿丙二酸，线粒体氧化还原状态的调节剂。这表明存在K+通道开放剂靶向的线粒体保护的K+电导非依赖性途径。因此，K+通道开放剂的心脏保护机制包括在复氧时直接减弱线粒体氧化应激。
K+ channel openers have been recently recognized for their ability to protect mitochondria from anoxic injury. Yet the mechanism responsible for mitochondrial preservation under oxidative stress is not fully understood. Here, mitochondria were isolated from rat hearts and subjected to 20-min anoxia, followed by reoxygenation. At reoxygenation, increased generation of reactive oxygen species (ROS) was associated with reduced ADP-stimulated oxygen consumption, blunted ATP production, and disrupted mitochondrial structural integrity coupled with cytochrome c release. The prototype K+ channel opener diazoxide markedly reduced mitochondrial ROS production at reoxygenation with a half-maximal effect of 29 muM. Diazoxide also preserved oxidative phosphorylation and mitochondrial membrane integrity, as indicated by electron microscopy and reduced cytochrome c release. The protective effect of diazoxide was reproduced by the structurally distinct K+ channel opener nicorandil and antagonized by 5-hydroxydecanoic acid, a short-chain fatty acid derivative and presumed blocker of mitochondrial ATP-sensitive K+ channels. Opener-mediated mitochondrial protection was simulated by the free radical scavenger system composed of superoxide dismutase and catalase. However, the effect of openers on ROS production was maintained in nominally K+-free medium in the presence or absence of the K+ ionophore valinomycin and was mimicked by malonate, a modulator of the mitochondrial redox state. This suggests the existence of a K+ conductance-independent pathway for mitochondrial protection targeted by K+ channel openers. Thus the cardioprotecive mechanism of K+ channel openers includes direct attenuation of mitochondrial oxidant stress at reoxygenation.