Resveratrol increase myocardial Nrf2 expression in type 2 diabetic rats and alleviate myocardial ischemia/reperfusion injury (MIRI)

Abstract

Background: Oxidative stress is one of the main factors that increases reperfusion injury in the diabetic heart. Resveratrol could decrease oxidation and promote antioxidant factor expression. Nrf2 is an important endogenous antioxidant. making the heart more resistant to ischemic injury. As Nrf2 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of Nrf2 in the diabetic heart may overcome its increased susceptibility to ischemic injury.

Methods: A total of 50 diabetic rats were randomly divided into five groups: the sham operation group (DM + sham), the MIRI group (DM + MI/R), the resveratrol treatment group (DM + MI/R + RSV), the resveratrol + ex527 (SIRT1 inhibitor) group (DM + MI/R + RSV + ex527), and the resveratrol + LY294002 (Akt inhibitor) group (MD + MI/R + RSV + LY294002). Another 20 normal rats were randomly divided into two groups: the sham-operated group (CON + sham) and the myocardial ischemia-reperfusion group (CON + MI/R). A type 2 diabetes model was induced by a high-fat diet-fed and intraperitoneal injection of streptozotocin (STZ). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasma were collected to measure the creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA) level, glutathione (GSH) level, and superoxide dismutase (SOD) activity. Pathologic changes in myocardial tissues were observed by Hematoxylin and eosin (HE) straining. SIRT1, p-GSK3β, Nrf2, HO-1 protein expressions were measured by western blot.

Results: Compared with the control (CON) group, the diabetic (DM) group had more severe myocardial injury, higher oxidative stress index increase, and a more reduced expression of Nrf2 in the myocardium. After supplementing with resveratrol, the myocardial damage was reduced and the oxidative stress index decreased in the DM group, while the Nrf2 in the myocardium was increased. It also was found that inhibition of SIRT1 also partially inhibited the expression of Nrf2 and the corresponding antioxidant factor HO-1. Decreased expression of p-GSK3β by Akt inhibitors also partially inhibited Nrf2 and HO-1 expression.

Conclusions: Resveratrol can enhance the expression of Nrf2 in a diabetic heart by stimulating SIRT1 or inhibiting GSK3β, alleviating myocardial oxidative stress, and improving ischemia-reperfusion injury.

Keywords: GSK3β; Nrf2; Resveratrol; SIRT1; diabetes; myocardial ischemia/reperfusion.