Inhibition of the Let-7 Family MicroRNAs Induces Cardioprotection Against Ischemia-Reperfusion Injury in Diabetic Rats

Abstract

The expression of the let-7 family microRNAs in the myocardium of streptozotocin-induced diabetic rats was measured, and the cardioprotection of inhibition of let-7 microRNAs against ischemia-reperfusion injury was investigated. The diabetic rats and nondiabetic rats were subjected to 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion. The infarct size was determined by triphenyltetrazolium chloride staining. The expression of let-7 was measured by quantitative real-time polymerase chain reaction, and expressions of insulin receptor (InsR), insulin-like growth factor-1 receptor (IGF-1R), glucose transporter type 4 (GLUT4), and the phosphorylation states of Akt and the mammalian target of rapamycin (mTOR) were analyzed using Western blot. Inhibition of let-7 was performed by local transfection of lentivirus gene transfer vectors containing let-7 antimiR. Compared with nondiabetic rats, the expression of let-7 was enhanced in the myocardium of diabetic rats (p= 0.029), whereas expressions of InsR, IGF-1R, and GLUT4 were decreased after ischemia-reperfusion (p < 0.01). Local transfection of the let-7 antimiR markedly inhibited the expression of let-7 (p= 0.038) and improved expressions of InsR, IGF-1R, and GLUT4 in the myocardium of diabetic rats (p < 0.01). The infarct size of diabetic rats was much higher than that of nondiabetic rats (p < 0.0001). Transfection of the let-7 antimiR significantly reduced the infarct size of diabetic rats (p < 0.0001), and such an antiinfarct effect was abolished completely by pretreatment of Akt inhibitor LY294002 or mTOR inhibitor rapamycin. Inhibition of the let-7 family microRNAs improves glucose uptake and insulin resistance in the diabetic myocardium and induces cardioprotection against ischemia-reperfusion injury through Akt and mTOR pathways.