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目的探讨代谢性胰岛素抵抗(Insulin resistance,IR)对肥胖大鼠心肌缺血/再灌注(Myocardial ischemia/reperfusion,MI/R)耐受性的影响。方法将Wistar大鼠随机分为对照组(Cont组)、罗格列酮组(Rosi组)和肥胖组(Obes组),Rosi组给予高脂饲料喂养的同时灌胃罗格列酮,Obes组给予高脂饲料喂养,并灌胃相同剂量的生理盐水。检测各组大鼠血浆中各项生化指标、心肌组织总甘油三酯(Triglyceride,TG)的含量及胰岛素敏感性。制备大鼠MI/R模型,并取Obes组和Rosi组大鼠,输注磷脂酰肌醇-3羟基激酶(PI3K)抑制剂渥曼青霉素,分别记为Obwt组和Wort组,检测各组大鼠心脏血流动力学指标的变化;伊文蓝染色测定大鼠心肌缺血面积,2,3,5一氯化三苯四氮唑(TTC)染色测定心肌梗死面积;原位末端标记凋亡细胞(TUNEL)法分析心肌细胞凋亡;Western blot法检测心肌中PKB/Akt和GluT-4蛋白的表达水平。结果 MI/R前,与Cont组相比,Obes组大鼠心肌TG及血浆中游离脂肪酸(Free fatty acid,FFA)、TG和空腹胰岛素(Fasting insulin,FINS)水平均显著升高(P<0.05或P<0.01),葡萄糖输注率(Glucose infusion rate,GIR)显著降低(P<0.01);而Rosi组大鼠血浆中TG、FFA和FINS水平较Obes组显著降低(P<0.01),GIR显著升高(P<0.01)。与Cont组相比,Obes组大鼠MI/R后,心功能恢复差,梗死面积扩大,心肌细胞凋亡增多,并伴PKB/Akt和GluT-4表达水平下降;Rosi组与Obes组比,MI/R恢复能力增强,梗死面积缩小,细胞凋亡减少,PKB/Akt和GluT-4表达水平增加。Wort组大鼠可逆转Rosi组的抗凋亡作用,下调PKB/Akt和GluT-4的表达水平;而Obwt组大鼠MI/R后,心功能、心肌细胞凋亡数及PKB/Akt和GluT-4表达水平与Obes组相比,差异均无统计学意义(P>0.05)。结论肥胖大鼠心肌IR增加了MI/R时的易损性,与PI3K-PKB-GluT-4信号通路下调、心肌细胞凋亡增加及心功能恶化密切相关。
Objective To investigate the effect of insulin resistance (Insulin resistance, IR) on the myocardial ischemia / reperfusion (MI / R) tolerance in obese rats. Methods The Wistar rats were randomly divided into control group (Cont group), rosiglitazone group (Rosi group) and obes group (Obes group). Rosi group was given high fat diet while rosiglitazone and obes group Give high-fat feed, and the same dose of saline. All the biochemical indexes in plasma, triglyceride (TG) content and insulin sensitivity in each group were detected. The rat model of MI / R was established. The rats in Obes group and Rosi group were given wortmannin, a phosphatidylinositol-3-hydroxy kinase (PI3K) inhibitor, and were respectively recorded as Obwt group and Wort group. Myocardial infarct size was measured by 2,3,5-trichloro-tetrachloro-tetrazolium chloride (TTC) staining. Evoked end-labeled apoptotic cells (TUNEL) method was used to analyze cardiomyocyte apoptosis. Western blot was used to detect the expression of PKB / Akt and GluT-4 protein in myocardium. Results Compared with the Cont group, the level of myocardial TG and the level of free fatty acid (FFA), fasting insulin (TG) and fasting insulin (FINS) in Obes group were significantly increased after MI / R (P <0.01 or P <0.01), and the glucose infusion rate (GIR) decreased significantly (P <0.01). The levels of TG, FFA and FINS in the Rosi group were significantly lower than those in the Obes group (P <0.01) Significantly increased (P <0.01). Compared with the Cont group, the heart function recovery, infarct size and cardiomyocyte apoptosis in obes group were significantly decreased after MI / R in the rats of the Obes group, accompanied with the decrease of the expression of PKB / Akt and GluT-4. Compared with the Obes group, MI / R enhanced capacity, reduced infarct size, decreased apoptosis, PKB / Akt and GluT-4 expression levels increased. The Wort group could reverse the anti-apoptotic effect of Rosi group and down-regulate the expression of PKB / Akt and GluT-4. However, after MI / R in Obwt group, the cardiac function, cardiomyocyte apoptosis and PKB / Akt and GluT -4 expression level compared with the Obes group, the difference was not statistically significant (P> 0.05). Conclusion Myocardial IR increased the MI / R vulnerability in obese rats, which is closely related to the downregulation of PI3K-PKB-GluT-4 signaling pathway, the increase of cardiomyocyte apoptosis and the deterioration of cardiac function.