Second Department of Internal Medicine, Kansai Medical University, Moriguchi City, Japan.
J Mol Cell Cardiol. 2011 Mar;50(3):534-44. doi: 10.1016/j.yjmcc.2010.12.010. Epub 2010 Dec 20.
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.
糖尿病心脏易受缺血/再灌注 (I/R) 损伤，这与氧化应激增加有关。尽管氧化应激会导致诱导型一氧化氮合酶 (iNOS) 的上调，但 iNOS 在糖尿病心脏的 I/R 损伤中的作用仍知之甚少。由于 iNOS 衍生的一氧化氮 (NO) 在对抗 I/R 损伤的心脏保护中起着至关重要的作用，我们假设抑制 iNOS 解偶联会恢复糖尿病心脏对 I/R 损伤的耐受性。本研究表明，在糖尿病大鼠心脏分离的心脏中，在 I/R 之前用 NOS 辅助因子四氢生物蝶呤 (BH4) 处理可减少 iNOS 衍生的超氧化物生成，并增加 NO 的生物利用度。这与 I/R 后梗死面积减小和左心室 (LV) 功能改善有关。BH4 的心脏保护作用被硫醇还原剂二硫苏糖醇 (DTT) 消除，但不是 NO 敏感的鸟苷酸环化酶抑制剂 ODQ，表明 iNOS 衍生的 NO 介导的心脏保护作用是通过蛋白质 S-亚硝基化而不是 cGMP 依赖性信号转导发生在糖尿病心脏。事实上，BH4 处理可增加糖尿病心脏中的蛋白质 S-亚硝基化，并被 DTT 抑制。这些结果表明，抑制 iNOS 解偶联通过增强糖尿病大鼠心脏中的蛋白质 S-亚硝基化来揭示对 I/R 损伤的耐受性。
