Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition.
Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition.
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DOI：
10.1161/circulationaha.108.791533
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发表时间：
2008-11-04
期刊：
影响因子：
37.8
通讯作者：
Bhatnagar A
中科院分区：
文献类型：
--
作者：
West MB;Rokosh G;Obal D;Velayutham M;Xuan YT;Hill BG;Keith RJ;Schrader J;Guo Y;Conklin DJ;Prabhu SD;Zweier JL;Bolli R;Bhatnagar A
诱导型一氧化氮合酶（iNOS）是缺血预处理（PC）后期的强制性介质，但其心脏保护作用的机制尚不清楚。此外，肌细胞中iNOS的持续升高是否对缺血-再灌注损伤提供慢性保护尚不清楚。转基因（TG）小鼠（α-肌球蛋白重链启动子）的组成性过表达iNOS不会引起收缩功能障碍，也不会影响线粒体呼吸或生物发生，但在冠状动脉闭塞30分钟和再灌注24小时的小鼠中，iNOS会显著降低梗死面积。与野生型（WT）心脏相比，分离的inos转基因（TG）心脏缺血30分钟后再灌注40分钟，表现出更好的收缩恢复，更小的梗死面积，更少的2-脱氧-[3H]-葡萄糖（DOG）线粒体夹带。在iNOS-TG心脏中，再灌注诱导的NAD+损失和线粒体细胞色素c释放减弱，表明线粒体通透性转变（MPT）降低。在离体缺血再灌注前24小时，NO供体NOC-22可阻止离体线粒体的通透性转变，mpt诱导的NAD+损失在WT小鼠中有所减少，但在iNOS-null小鼠中没有。白术皂苷不消除inos介导的心脏保护作用。再灌注诱导的氧自由基产生（通过电子顺磁共振波谱测量）在iNOS- tg心脏中减弱，而在MPT抑制剂环孢素a处理的WT心脏中增加。心肌细胞限制iNOS的表达提供持续的心脏保护。这与再灌注诱导的氧自由基减少以及线粒体肿胀和通透性转变的抑制有关。
Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning (PC) but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia-reperfusion injury. Constitutive overexpression of iNOS in transgenic (TG) mice (α-myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but profoundly decreased infarct size in mice subjected to 30 min of coronary occlusion and 24 h of reperfusion. In comparison with wild-type (WT) hearts, isolated iNOS-transgenic (TG) hearts subjected to ischemia for 30 min followed by 40 min of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[3H]-glucose (DOG). Reperfusion-induced loss of NAD+ and mitochondrial release of cytochrome c were attenuated in iNOS-TG hearts, indicating reduced mitochondrial permeability transition (MPT). The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and MPT-induced NAD+ loss was decreased in WT but not iNOS-null mice treated with the NO donor DETA/NO, 24 h before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-TG hearts and was increased in WT hearts treated with the MPT inhibitor cyclosporin A. Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.