| BackgroudSeveral recent landmark studies showed that GIK significantly reduced the mortality of patients with acute myocardial infarction. Our previous studies demonstrated that insulin, as the predominant protective component of the previously used GIK cocktail, reduced myocardial apoptotic death and consequently improved cardiac function after acute myocardial ischemia/reperfusion (MI/R) through the survival signaling, that is, phosphatidylinositol 3 kinase-Akt-endothelial nitric oxide synthase (PI3K-Akt-eNOS) signaling pathway. On the other hand, myocardial salvage induced by reperfusion therapies such as thrombolytic agents and PCI confers a benefit on the patients, whereas the improved survival of patients with MI has led to an increase in the number of patients suffering from heart failure. However, to date, the effect of insulin on prolonged post-MI heart falire (HF) remains largely unclear.AimsThe present study was aimed to investigate the effects of insulin treatments on the prolonged post-ischemic left ventricular remodeling and function.MethodsAdult male rats were subjected to left anterior descending coronary artery occlusion and were randomized to receive one of the following treatments: saline (4 ml/kg/h i.v. injection beginning 10 min before the ischemia and continuing for 2 h), early insulin treatment (50 U/L, i.v. injection following the same routine, and hypodermic injection of insulin (0.5U/ml, 1ml/kg/d) for 7 d after the ischemia surgery) or late insulin treatment (the same dose and routine of insulin starting at 1 wks after the surgery). The parameters of echocardiogram were investigated before the operation and 1, 4 and 8 weeks after the operation. 4 wks after MI, the parameters of hemodynamics were detected, the cross-sectional area of cardiomyocytes were mesured with HE staining, the collagen volume fraction and infarct size were mesured with Masson staining. Hydroxyproline concentration were detected. Apoptotic cells were detected by the TUNEL assay and the activity of caspase-3 was measured. Other three experiment groups were performed to evaluate systemic insulin sensitivity and insulin stimulated noninfarcted myocardial FDG uptake: 1) normal (normal rats without operation); 2) MI 1 d (rats 1 day after myocardial infarction); 3) MI 1 wk (rats 1 week after myocardial infarction). FPG, FIN and insulin stimulated noninfarcted myocardial FDG uptake were mesured. Insulin stimulated p-Akt/Akt and p-p38 MAPK/p38 MAPK expression were detected by western blotting.Results1. Early but not late insulin treatment significantly attenuated myocardial injury and improved cardiac function as evidenced by reduced infarct size, increased LVEF and LVFS at 1 wk, 4 wk and 8 wk after MI, increased LVDP and±LV dP/dtmax 4 wks after MI(n=6, P<0.05 or P<0.01 and n=8-11, P<0.05).2. Early but not late insulin treatment significantly alleviated cardiac remodeling post-myocardial infarction as evidenced by increased LVESD at 1 wk, 4 wk and 8 wk after MI, decreased collagen volume fraction and collagen content 4 wks after MI(n=6, P<0.05).3. Early but not late insulin treatment significantly attenuated myocardial apoptosis as evidenced by reduced caspase-3 activity and apoptosis index 4 wks after MI(n=3, P<0.05).4. There were no signi?cant differences in FPG, FIN and HOMA -IR among the additional three experiment groups(n=6, P>0.1). However, insulin stimulated noninfarcted myocardial FDG uptake was significantly lower in vivo 1 wk after MI compared with MI 1 d and normal group(n=6, P<0.01). Insulin stimulation at 1 d after MI significantly increased the phosphorylation of Akt while insulin stimulation at 1 wk after MI significantly increased the phosphorylation of p38 MAPK (n=3, P<0.01).ConclusionThe present study demonstrates, for the first time, that early but not late insulin treatment improves prolonged post-ischemic cardiac structural and functional changes, anti-apoptosis survival signaling and another p38 MAPK signaling contribute to the different effects of insulin. |
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