Role of PI3K/Akt/Nrf2 signaling pathway in resveratrol preconditioning-induced cardioprotection in diabetic rats

Objective To evaluate the role of phosphatidylinositol-3-kinase/protein kinase B/nuclear factor erythroid 2-related factor 2 (PI3K/Akt/Nrf2) signaling pathway in resveratrol preconditioning-induced cardioprotection in diabetic rats. Methods Clean-grade healthy male Sprague-Dawley rats, aged 2-3 months, weighing 240-280 g, were used in the study.The diabetes model was established by intraperitoneal injection of streptozotocin 30 mg/kg once a day for 7 consecutive days.Forty diabetic rats were selected and divided into 4 groups (n=10 each) according to the random number table method: sham operation group (S group), myocardial ischemia-reperfusion (I/R) group (I/R group), resveratrol plus myocardial I/R group (Res+ I/R group), and PI3K inhibitor LY294002 plus resveratrol plus myocardial I/R group (LY+ Res+ I/R group). The myocardial I/R injury model was established by ligating the left anterior descending coronary artery for 30 min followed by 120-min reperfusion in anesthetized rats.Resveratrol 20 mg/kg was intraperitoneally injected once a day for 7 consecutive days at one week before surgery in Res+ I/R and LY+ Res+ I/R groups.LY294002 1.5 mg/kg was intraperitoneally injected at 30 min before operation in LY+ Res+ I/R group.After 120 min of reperfusion, blood samples were taken for determination of serum creatine kinase-MB (CK-MB) and lactic dehydrogenase (LDH) concentrations (by enzyme-linked immunosorbent assay), and myocardial tissues at the ischemic area were obtained for determination of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA)levels (by enzyme-linked immunosorbent assay) and expression of Akt, phosphorylated Akt (p-Akt), glycogen synthase kinase 3β (GSK3β), phosphorylated GSK3β (p-GSK3β) and Nrf2 (by Western blot). Results Compared with group S, serum CK-MB and LDH concentrations were significantly increased, the SOD and GSH levels were decreased, the MDA level was increased, and the expression of p-Akt and p-GSK3β was down-regulated in I/R group (P<0.05). Compared with I/R group, serum CK-MB and LDH concentrations were significantly decreased, the SOD and GSH levels were increased, the MDA level was decreased, and the expression of p-Akt, p-GSK3β and Nrf2 was up-regulated in Res+ I/R group (P<0.05). Compared with Res+ I/R group, serum CK-MB and LDH concentrations were significantly increased, the SOD and GSH levels were decreased, the MDA level was increased, and the expression of p-Akt, p-GSK3β and Nrf2 was down-regulated in LY+ Res+ I/R group (P<0.05). Conclusion The mechanism of resveratrol preconditioning-induced cardioprotection is related to activating PI3K/Akt/Nrf2 signaling pathway and inhibiting oxidative stress responses in diabetic rats. Key words: Myocardial reperfusion injury; Diabetes mellitus; Phenols; 1-phosphatidylinositol 3-kinase; Protein-serine-threonine kinases; NF-E2-related factor 2