Resveratrol Prevents Diabetic Cardiomyopathy By Increasing Nrf2 Expression And Transcriptional Activity

Background:Diabetes mellitus(DM)is one of the most common metabolic disorders in the world.Among the many complications of diabetes,diabetic cardiomyopathy is the leading cause of death in diabetic patients.Diabetic cardiomyopathy refers to diabetic myocardial injury that cannot be explained by coronary artery disease,hypertension,and valvular disease.The pathological changes are mainly microvascular lesions,leading to changes in myocardial structure and function,such as myocardial cell apoptosis,myocardial interstitial fibrosis and myocardial perfusion abnormalities.The clinical features of diabetic cardiomyopathy include early diastolic dysfunction and late systolic dysfunction,which leads to reduced left ventricular function and subsequent difficulty in breathing.At present,studies on the pathogenesis of diabetic cardiomyopathy mostly focus on oxidative stress,myocardial cell apoptosis,endoplasmic reticulum stress,myocardial insulin resistance,endothelial dysfunction,mitochondrial dysfunction and autophagy.However,it is generally believed that oxidative stress is the central link in the pathogenesis of diabetic cardiomyopathy.Nrf2 is a member of the CNC protein family.This protein family is the basic regulator of antioxidant activity and electrophilic signaling.When cells are stimulated by oxidative stress or electrophilic compounds,Nrf2 promotes the transcription of downstream antioxidant and detoxifying enzymes by combining with antioxidant response elements(AREs).Because of the large number of antioxidant factors and detoxifying enzymes downstream of Nrf2,it forms a powerful network of antioxidant and detoxification,preventing further damage to cells and organisms.So finding an effective activator is crucial for the further activation of Nrf2 expression and transcriptional activity.CTGF is an important factor in vascular fibrosis and cardiac hypertrophy.Oxidative stress also increases the expression of CTGF,and inhibiting oxidative stress by activating NRF2 may be an effective way to reduce the expression of CTGF.Resveratrol(RES)is a polyphenolic substance widely found in grape skins,seeds,nuts,giant knotweed and other plants.Current research shows that it has antioxidative stress and antihypertensive effects.However,the protective effect of resveratrol on diabetic cardiomyopathy and its mechanism are still controversial This study further explored the beneficial effect of resveratrol on the activation of Nrf2 and its protective effect on diabetes.Objective:This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms.Method:Type 1 diabetes mellitus(DM)in FVB mice was induced by several intraperitoneal injections of a low-dose of streptozotocin.Hyperglycemic and age-matched control mice were administered resveratrol(10 mg/kg per day)for 1 month and subsequently monitored for an additional6 months.Mice were assigned to four groups: Control,resveratrol,DM,and DM/resveratrol.Cardiac function and blood pressure were assessed at1,3 and 6 months after DM induction.Oxidative damage and cardiac fibrosis were analyzed by histopathology,real-time PCR,and Western blot.Result:Mice in the DM group exhibited increased blood glucose levels,cardiac dysfunction,and high blood pressure at 1,3 and 6 months after DM induction.Resveratrol did not significantly affect blood glucose levels;however,resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice.Resveratrol also reduced DM-induced fibrosis.In addition,DM hearts exhibited increased oxidative damage,as evidenced by elevated accumulation of 3-nitrotyrosine and 4-hydroxynonenal,which were both attenuated by resveratrol.Mechanistically,resveratrol increased Nrf2 expression and transcriptional activity,as well as Nrf2’s downstream anti-oxidative targets.Conclusion:We demonstrated that resveratrol prevents DM-induced cardiomyopathy,in part,by increasing Nrf2 expression and transcriptional activity.Resveratrol can reduce oxidative stress and inhibit cardiac hypertrophy and vascular fibrosis caused by CTGF by up-regulating Nrf2,which hinders the occurrence and development of diabetic cardiomyopathy.