Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.01173.2005
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发表时间：
2006-12-01
影响因子：
4.8
通讯作者：
Lefer, David J.
中科院分区：
文献类型：
--
作者：
Duranski, Mark R.;Elrod, John W.;Lefer, David J.
以往的研究表明，内皮型一氧化氮合酶（eNOS）是缺血再灌注（I-R）损伤的重要信号分子。在I-R的肝和心肌模型中，eNOS衍生的NO的缺乏已被证明会加重损伤。我们假设转基因eNOS过表达（eNOS TG）可以减轻肝脏I-R损伤。我们进行了两个品系的eNOS-TG小鼠45分钟的肝缺血和5小时的再灌注。与野生型同窝仔相比，这两种菌株均免受肝I-R损伤。由于这种保护的机制尚不清楚，因此通过使用可溶性鸟苷酸环化酶（sGC）和血红素加氧酶-1（HO-1）酶的抑制剂和激活剂进行了额外的研究。在野生型小鼠中，用1H[1，2，4]恶二唑并[4，3-a]喹喔啉-1-酮（ODQ）阻断sGC和用锌（III）次卟啉IX-2，4-二乙二醇（ZnDPBG）阻断HO-1可增加肝I-R损伤，而在野生型小鼠中，激活这些酶可显著减弱I-R损伤。有趣的是，ODQ取消了eNOS过表达的保护作用，而ZnDPBG没有效果。这些结果表明，在eNOS-TG小鼠的肝脏保护可能是通过sGC-cGMP通路的NO信号转导介导的一部分，是独立的HO-1信号转导途径。
Previous studies have shown that endothelial nitric oxide ( NO) synthase (eNOS)derived NO is an important signaling molecule in ischemia-reperfusion (I-R) injury. Deficiency of eNOS-derived NO has been shown to exacerbate injury in hepatic and myocardial models of I-R. We hypothesized that transgenic overexpression of eNOS (eNOS-TG) would reduce hepatic I-R injury. We subjected two strains of eNOS-TG mice to 45 min of hepatic ischemia and 5 h of reperfusion. Both strains were protected from hepatic I-R injury compared with wild-type littermates. Because the mechanism for this protection is still unclear, additional studies were performed by using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC with 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and HO-1 with zinc (III) deuteroporphyrin IX-2,4-bisethyleneglycol (ZnDPBG) in wildtype mice increased hepatic I-R injury, whereas pharmacologically activating these enzymes significantly attenuated I-R injury in wildtype mice. Interestingly, ODQ abolished the protective effects of eNOS overexpression, whereas ZnDPBG had no effect. These results suggest that hepatic protection in eNOS-TG mice may be mediated in part by NO signaling via the sGC-cGMP pathway and is independent of HO-1 signal transduction pathways.