【摘要】 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。更多还原

【Abstract】 Objective To investigate the effect of metabolic insulin resistance(IR) on tolerance of obese rats to myocardial ischemia / reperfusion(MI / R).Methods Wistar rats were randomly divided into control(Cont),rosiglitazone(Rosi) and obese(Obes) groups.The rats in Cont group were fed with common forage,while those in Rosi group were fed with high fat diet and treated with rosiglitazone by gastric lavage,and those in Obes group were fed with high fat diet and treated with physiological saline at the same dosage as that of rosiglitazone.The rats in various groups were determined for biochemical indexes in plasma,the triglyceride(TG) content in myocardial tissue and the sensitivity to insulin.MI / R model was established by using the rats in various groups,while the rats in Obes and Rosi groups were intravenously infused with wortmannin,an inhibitor of PI3K,and served as Obwt and Wort groups respectively.The rats in various groups were determined for hemodynamics in heart,measured for area of MI by Evans blue staining and that of myocardial infarction by TTC staining,analyzed for apoptosis of myocardial cells by TUNEL method,and for expression levels of PKB / Akt and GluT-4 proteins by Western blot method.Results Before MI / R,the TG in myocardial tissue as well as free fatty acid(FFA),TG and fasting insulin(FINS) levels in plasma of rats in Obes group increased significantly as compared with those in Cont group(P < 0.05 or P < 0.01),while glucose infusion rate(GIR) decreased significantly(P < 0.01);the TG,FFA and FINS levels in plasma of rats in Rosi group decreased significantly(P < 0.01) while GIR increased significantly(P < 0.01) as compared with those in Obes group.However,after MI / R,the cardiac function of rats in Obes group was weak as compared with that in Cont group,while the area of myocardial infarction was enlarged,the apoptotic myocardial cells increased,and the expression levels of PKB / Akt and GluT-4 decreased;the cardiac function of rats in Rosi group was improved as compared with that in Obes,while the area of myocardial infarction was reduced,the apoptotic myocardial cells decreased,and the expression levels of PKB / Akt and GluT-4 increased.Wortmannin reversed the resistance to apoptosis of myocardial cells of rats in Rosi group,and down-regulated the expressions of PKB / Akt and GluT-4.However,no significant differences were observed in cardiac functions,numbers of apoptotic myocardial cells as well as expression levels of PKB / Akt and GluT-4 between Obwt and Obes groups(P > 0.05).Conclusion IR of obese rats increased the fragility to MI / R,which was closely related to down-regulation of PI3K-PKB-GluT-4 signaling pathway,increase of apoptotic myocardial cells and degradation of cardiac function.更多还原