Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress.
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.
Ji
Lele
L
Dept. of Physiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Fu
Feng
F
Zhang
Lihua
L
Liu
Wenchong
W
Cai
Xiaoqing
X
Zhang
Lei
L
Zheng
Qiangsun
Q
Zhang
Haifeng
H
Gao
Feng
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D004562:Electrocardiography / Q000187:drug effects; D006334:Heart Function Tests; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D026361:Reactive Nitrogen Species; C002744:3-nitrotyrosine; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D053148:Caspase 3