Protection of cardiac mitochondria by diazoxide and protein kinase C: Implications for ischemic preconditioning
Protection of cardiac mitochondria by diazoxide and protein kinase C: Implications for ischemic preconditioning
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DOI：
10.1073/pnas.052713199
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发表时间：
2002-03-05
影响因子：
11.1
通讯作者：
Weiss, JN
中科院分区：
文献类型：
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作者：
Korge, P;Honda, HM;Weiss, JN
线粒体ATP敏感K（mitoK(ATP)）通道在缺血预处理中保护心脏免受损伤中起核心作用。在分离的线粒体中，暴露于额外的线粒体Ca， P-i升高和缺氧来模拟缺血条件，选择性mitoK（ATP）通道激动剂二氮氧化物（25-50 muM）通过防止线粒体通透性转变（MPT）和细胞色素c从膜间空间损失有效地减少线粒体损伤。这两种作用都被选择性mitoK（ATP）拮抗剂5-羟癸酸酯完全阻断。在电子传递支持膜电位（Deltapsi(m)）的能力降低和内膜漏度适度增加的条件下，对ca诱导的MPT的保护作用最为明显。在这些条件下，mitoK（ATP）通道活性强烈调节Deltapsi(m)，而二氮氧化物通过抑制Ca摄取的驱动力来阻止MPT。Phorbol 12-肉豆蔻酸酯13-乙酸酯模拟了二氮氧化物的保护作用，除非5-羟基癸酸酯存在，这表明蛋白激酶C激活也通过激活mitoK（ATP）通道来保护线粒体。由于心肌功能的恢复最终是必需的，这些结果可以解释mitoK（ATP）通道激活如何通过保护线粒体在缺血/再灌注期间通过一个关键的脆弱性窗口来模拟缺血预处理。
Mitochondrial ATIP-sensitive K (mitoK(ATP)) channels play a central role in protecting the heart from injury in ischemic preconditioning. In isolated mitochondria exposed to elevated extra mitochondrial Ca, P-i, and anoxia to simulate ischemic conditions, the selective mitoK(ATP) channel agonist diazoxide (25-50 muM) potently reduced mitochondrial injury by preventing both the mitochondrial permeability transition (MPT) and cytochrome c loss from the intermembrane space. Both effects were blocked completely by the selective mitoK(ATP) antagonist 5-hydroxydecanoate. The protective effect against Ca-induced MPT was most evident under conditions in which the ability of electron transport to support membrane potential (Deltapsi(m)) was decreased and inner membrane leakiness was increased moderately. Under these conditions, mitoK(ATP) channel activity strongly regulated Deltapsi(m), and diazoxide prevented MPT by inhibiting the driving force for Ca uptake. Phorbol 12-myristate 13-acetate mimicked the protective effects of diazoxide, unless 5-hydroxydecanoate was present, indicating that protein kinase C activation also protects mitochondria by activating mitoK(ATP) channels. Because At m recovery ultimately is required for heart functional recovery, these results may explain how mitoK(ATP) channel activation mimics ischemic preconditioning by protecting mitochondria as they pass through a critical vulnerability window during ischemia/reperfusion.