The opposite effects of nitric oxide donor, S-nitrosoglutathione, on myocardial ischaemia/reperfusion injury in diabetic and non-diabetic mice
The opposite effects of nitric oxide donor, S-nitrosoglutathione, on myocardial ischaemia/reperfusion injury in diabetic and non-diabetic mice
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一氧化氮供体 S-亚硝基谷胱甘肽对糖尿病和非糖尿病小鼠心肌缺血/再灌注损伤的相反作用
DOI：
10.1111/1440-1681.12781
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发表时间：
2017-08-01
影响因子：
2.9
通讯作者：
Tao, Ling
中科院分区：
文献类型：
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作者：
Liu, Yi;Xia, Chenhai;Tao, Ling
一氧化氮是一种有效的抗细胞凋亡和心脏保护分子。然而，最近的研究表明，eNOS的过表达加剧了糖尿病动物的肝损伤。糖尿病是否也可能改变缺血/再灌注心脏NO的生物活性尚不清楚。本实验旨在确定一氧化氮供体s -亚硝基谷胱甘肽对糖尿病和非糖尿病心肌缺血/再灌注（MI/R）损伤是否有不同的影响。通过多次腹腔注射低剂量链脲佐菌素（STZ）诱导小鼠进入糖尿病状态。对照组和糖尿病小鼠分别缺血30分钟和再灌注3、24小时。在再灌注前10分钟，糖尿病和非糖尿病小鼠腹腔注射s -亚硝基谷胱甘肽（GSNO，一氧化氮供体，1 μ mol/kg）。GSNO通过改善心功能、减少梗死面积和减少心肌细胞凋亡来减轻非糖尿病小鼠的MI/R损伤。相比之下，GSNO不但不能减轻糖尿病小鼠的心肌梗死/心肌梗死损伤，反而加重了心肌梗死/心肌梗死损伤。机械上，与非糖尿病小鼠相比，糖尿病小鼠的心脏表现出更高的硝化/氧化应激水平，通过测量过氧亚硝酸盐的形成。再灌注前10分钟，GSNO与EUK134（一种过氧亚硝酸盐清除剂）或mte -2- pyp5（一种超氧化物歧化酶模拟物）或Apocynin（一种NADPH氧化酶抑制剂）共同给药，可显著降低心肌梗死/R诱导的过氧亚硝酸盐形成和心肌梗死/R损伤。总的来说，本研究首次证明糖尿病可能导致超氧化物过量产生，增加NO失活和过氧亚硝酸盐的形成，从而将GSNO从心脏保护分子转化为心脏毒性分子。
Nitric oxide is a potent anti-apoptotic and cardioprotective molecule in healthy animals. However, recent study demonstrates that overexpression of eNOS exacerbates the liver injury in diabetic animals. whether diabetes may also alter NO's biologic activity in ischaemic/reperfused heart remains unknown. The present experiment was designed to determine whether the nitric oxide donor, S-nitrosoglutathione, may exert different effects on diabetic and non-diabetic myocardial ischaemia/reperfusion (MI/R) injury. Diabetic state was induced in mice by multiple intraperitoneal injections of low-dose streptozotocin (STZ). The control or diabetic mice were subjected to 30 minutes ischaemia and 3 or 24 hours reperfusion. At 10 minutes before reperfusion, diabetic and non-diabetic mice were received an intraperitoneal injection of S-nitrosoglutathione (GSNO, a nitric oxide donor, 1 mu mol/kg). GSNO attenuated MI/R injury in non-diabetic mice, as measured by improved cardiac function, reduced infarct size and decreased cardiomyocyte apoptosis. In contrast, GSNO failed to attenuate but, rather, aggravated the MI/R injury in diabetic mice. Mechanically, the diabetic heart exhibited an increased nitrative/oxidative stress level, as measured by peroxynitrite formation, compared with non-diabetic mice. Co-administration of GSNO with EUK134 (a peroxynitrite scavenger) or MnTE-2-PyP5 (a superoxide dismutase mimetic) or Apocynin (a NADPH oxidase inhibitor) 10 minutes before reperfusion significantly decreased the MI/R-induced peroxynitrite formation and the MI/R injury. Collectively, the present study for the first time demonstrated that diabetes may cause superoxide overproduction, increase NO inactivation and peroxynitrite formation, and thus convert GSNO from a cardioprotective molecule to a cardiotoxic molecule.