Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress
Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress
复制标题
胰岛素通过减少氧化/硝化应激来减轻心肌缺血/再灌注损伤。
DOI：
10.1152/ajpendo.00623.2009
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发表时间：
2010-04-01
影响因子：
5.1
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Ji, Lele;Fu, Feng;Gao, Feng
众所周知，胰岛素具有心脏保护作用，胰岛素抵抗与心血管疾病密切相关。过氧亚硝酸盐（ONOO（-））的形成可能会引发氧化/硝化应激，并代表心脏病的主要细胞毒性作用。本研究旨在探讨胰岛素是否能减轻急性心肌缺血/再灌注（MI/R）时ONOO（-）的产生和氧化/硝化应激。成年雄性大鼠心肌缺血30 min，再灌注3 h。大鼠随机接受赋形剂、胰岛素或胰岛素加渥曼青霉素。在整个实验过程中监测动脉血压和左心室压力。胰岛素可显著改善MI/R后的心功能，减少心肌梗死、细胞凋亡和血肌酸激酶/乳酸脱氢酶水平。胰岛素治疗后心肌ONOO（-）形成明显减少。此外，胰岛素导致缺血/再灌注心肌组织中Akt和内皮型一氧化氮合酶（NO）磷酸化、NO产生和抗氧化能力显著增加。另一方面，胰岛素显着降低MI/R诱导的诱导型NOS（iNOS）和gp 91（phox）在心脏组织中的表达。wortmannin抑制胰岛素信号转导不仅阻断了胰岛素的心脏保护作用，而且显著减弱了胰岛素诱导的抗氧化/抗硝酸作用。此外，通过胰岛素或ONOO（-）清除剂尿酸抑制ONOO（-）形成可减少MI/R大鼠的心肌梗死面积。我们的结论是，胰岛素通过阻断ONOO（-）的形成，对MI/R损伤发挥心脏保护作用。增加的生理NO产生（通过eNOS磷酸化）和超氧阴离子还原有助于胰岛素的抗氧化/抗硝酸作用，其可以通过抑制磷脂酰肌醇3 '-激酶来逆转。这些结果为胰岛素的心血管作用机制提供了重要的新信息。
It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO(-)) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO(-) generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO(-) formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91(phox) expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO(-) formation by either insulin or an ONOO(-) scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO(-) formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3'-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.