Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart
Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart
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DOI：
10.1016/j.yjmcc.2010.12.010
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发表时间：
2011-03-01
影响因子：
5
通讯作者：
Iwasaka, Toshiji
中科院分区：
文献类型：
--
作者：
Okazaki, Toru;Otani, Hajime;Iwasaka, Toshiji
已知糖尿病心脏易受增加的氧化应激引起的缺血/再灌注（I/R）损伤。虽然氧化应激上调诱导型一氧化氮（iNOS），在糖尿病心脏I/R损伤的iNOS的作用一直知之甚少。由于iNOS衍生的一氧化氮（NO）在心肌保护中对I/R损伤起着至关重要的作用，我们假设抑制iNOS解偶联将恢复糖尿病心脏对I/R损伤的耐受性。本研究表明，iNOS衍生的超氧化物的产生减少，和NO的生物利用度增加，治疗与NOS-辅因子，四氢生物蝶呤（BH 4），在I/R之前，从糖尿病大鼠的心脏分离。这与I/R后梗死面积减少和左心室（LV）功能改善相关。BH 4的心脏保护作用通过用硫醇还原剂二硫苏糖醇（DTT）处理而消除，但不通过NO敏感性鸟苷酸环化酶抑制剂ODQ处理，这表明iNOS衍生的NO介导的心脏保护作用通过蛋白质S-亚硝基化而不是糖尿病心脏中的cGMP依赖性信号传导发生。事实上，蛋白质S-亚硝基化增加治疗与BH 4在糖尿病心脏和DTT抑制。这些结果表明，抑制iNOS解偶联unmasks耐受I/R损伤，通过增强蛋白S-亚硝基化在糖尿病大鼠心脏。(C)2010爱思唯尔有限公司版权所有。
The diabetic heart is known to be susceptible to ischemia/reperfusion (I/R) injury by increased oxidative stress. Although oxidative stress upregulates inducible nitric oxide (iNOS), the role of iNOS in I/R injury in the diabetic heart has been poorly understood. Because iNOS-derived nitric oxide (NO) plays a crucial role in cardioprotection against I/R injury, we hypothesized that inhibition of iNOS uncoupling would restore tolerance to I/R injury in the diabetic heart. The present study demonstrated that iNOS-derived superoxide generation was reduced, and that the NO bioavailability was increased, by treatment with the NOS-cofactor, tetrahydrobiopterin (BH4), before I/R in the hearts isolated from diabetic rats. This was associated with a reduction of infarct size and improvement of left ventricular (LV) function after I/R. The cardioprotective effect of BH4 was abrogated by treatment with a thiol reducing agent dithiothreitol (DTT), but not a NO-sensitive guanylyl cyclase inhibitor ODQ suggesting that iNOS-derived NO-mediated cardioprotection occurs through protein S-nitrosylation but not cGMP-dependent signaling in the diabetic heart. Indeed, protein S-nitrosylation was increased by treatment with BH4 in the diabetic heart and was inhibited by DTT. These results suggest that the inhibition of iNOS uncoupling unmasks tolerance to I/R injury through enhanced protein S-nitrosylation in the diabetic rat heart. (C) 2010 Elsevier Ltd. All rights reserved.