Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver.
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver.
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DOI：
10.1172/jci22493
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发表时间：
2005-05
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通讯作者：
Mark R. Duranski;James J. M. Greer;A. Dejam;S. Jaganmohan;N. Hogg;W. Langston;R. Patel;S. yet;Xunde Wang;C. Kevil;M. Gladwin;D. Lefer
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作者：
Mark R. Duranski;James J. M. Greer;A. Dejam;S. Jaganmohan;N. Hogg;W. Langston;R. Patel;S. yet;Xunde Wang;C. Kevil;M. Gladwin;D. Lefer
亚硝酸盐代表NO的循环和组织储存形式，其生物活化由黄嘌呤氧化还原酶的酶促作用、非酶促分解和脱氧血红蛋白、肌红蛋白和组织血红素蛋白的还原介导。由于从亚硝酸盐产生NO的速率是线性依赖于氧气和pH值的降低，我们假设亚硝酸盐将在缺血组织中还原为NO，并发挥NO依赖性保护作用。在小鼠肝脏和心脏缺血再灌注（I/R）损伤的情况下，给予亚硝酸钠溶液。在肝I/R，亚硝酸盐产生深刻的剂量依赖性的细胞坏死和凋亡的保护作用，观察到在接近生理亚硝酸盐浓度的高度显着的保护作用。在心肌I/R损伤中，亚硝酸盐使心肌梗死面积减少67%。与缺氧依赖性亚硝酸盐生物活化一致，亚硝酸盐在再灌注1-30分钟内还原为NO、S-亚硝基硫醇、N-硝基胺和铁亚硝基化血红素蛋白。亚硝酸盐介导的肝脏和心脏的保护依赖于NO的产生，而不依赖于eNOS和血红素加氧酶-1的活性。这些结果表明，亚硝酸盐是一种生物储备NO subserving在组织保护缺血损伤的关键功能。这些研究揭示了一种意想不到的新疗法，用于治疗心肌梗死、器官保存和移植以及休克状态等疾病。
Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitros-amines, and iron-nitrosylated heme proteins within 1-30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.