Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism.
Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism.
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DOI：
10.1152/ajpheart.00954.2003
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发表时间：
2004-08
期刊：
影响因子：
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通讯作者：
Qining Qin;Xi-ming Yang;Lin Cui;S. Critz;M. Cohen;Natasha C. Browner;T. Lincoln;J. Downey
中科院分区：
文献类型：
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作者：
Qining Qin;Xi-ming Yang;Lin Cui;S. Critz;M. Cohen;Natasha C. Browner;T. Lincoln;J. Downey
外源性一氧化氮（NO）通过依赖于活性氧的途径在心脏中触发预适应样效应。本研究检测了NO供体S-亚硝基-N-乙酰青霉胺（SNAP，2 μ M）触发其抗梗死作用的信号通路。离体兔心脏经历30分钟的局部缺血和随后的120分钟的再灌注。通过氯化三苯基四氮唑染色测定细胞大小。在SNAP治疗的心脏中，心肌梗死面积从对照心脏的30.5 +/- 3.0%降低到10.2 +/- 2.0%。用鸟苷酸环化酶阻断剂1H-[1，2，4]恶二唑[4，3-a]喹喔啉-1-酮（2 μ M）或线粒体ATP敏感性K（+）（mitoK（ATP））通道阻断剂5-羟基癸酸酯（200 μ M）包围SNAP输注完全阻断了SNAP的梗死保留效应（分别为34.3 +/- 3.8和32.2 +/- 1.6%梗死）。用8-（4-氯苯硫基）-鸟苷3 '，5'-环一磷酸（10 μ M）预处理心脏，这是一种细胞渗透性cGMP类似物，可激活蛋白激酶G，通过将梗死面积减少到危险区的7.5 +/- 1.1%来模拟SNAP的预处理效果。自由基清除剂N-（2-巯基丙酰基）甘氨酸（1 mM）或5-羟基癸酸（100 μ M;分别为28.9 +/- 2.7和33.6 +/- 5.0%的危险区梗死）消除了这种有益的作用。为了证实这些功能数据和SNAP对鸟苷酸环化酶-蛋白激酶G信号传导途径的影响，测量cGMP水平。SNAP使蛋白质水平从0.18 +/- 0.04增加到0.61 +/- 0.14 pmol/mg（P < 0.05）。这些数据表明，外源性NO触发的预处理效应，通过启动级联的事件，包括刺激鸟苷酸环化酶，使cGMP，激活蛋白激酶G，开放的mitoK（ATP）通道，并最终，生产活性氧。
Exogenous nitric oxide (NO) triggers a preconditioning-like effect in heart via a pathway that is dependent on reactive oxygen species. This study examined the signaling pathway by which the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 2 microM) triggers its anti-infarct effect. Isolated rabbit hearts experienced 30 min of regional ischemia and 120 min of subsequent reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining. Infarct size was reduced from 30.5 +/- 3.0% of the risk zone in control hearts to 10.2 +/- 2.0% in SNAP-treated hearts. Bracketing the SNAP infusion with either the guanylyl cyclase blocker 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (2 microM) or the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel blocker 5-hydroxydecanoate (200 microM) completely blocked the infarct-sparing effect of SNAP (34.3 +/- 3.8 and 32.2 +/- 1.6% infarction, respectively). Pretreatment of hearts with 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (10 microM), which is a cell-permeable cGMP analog that activates protein kinase G, mimicked the preconditioning effect of SNAP by reducing infarct size to 7.5 +/- 1.1% of the risk zone. This salutary effect was abolished by either the free radical scavenger N-(2-mercaptopropionyl)glycine (1 mM) or 5-hydroxydecanoate (100 microM; 28.9 +/- 2.7 and 33.6 +/- 5.0% infarction of the risk zone, respectively). To confirm these functional data and the effect of SNAP on the guanylyl cyclase-protein kinase G signaling pathway, cGMP levels were measured. SNAP increased the level from 0.18 +/- 0.04 to 0.61 +/- 0.14 pmol/mg of protein (P < 0.05). These data suggest that exogenous NO triggers the preconditioning effect by initiating a cascade of events including stimulation of guanylyl cyclase to make cGMP, activation of protein kinase G, opening of mitoK(ATP) channels, and, finally, production of reactive oxygen species.