Resveratrol Against Diabetic Hyperglycemia-induced Myocardial Injury:protective Effect And Mechanism

Background and purposeDiabetes mellitus(DM)is a prevalent metabolic disease characterized primarily by hyperglycemia,with a global prevalence of 4%to 17%and projected to affect 693 million adults worldwide by 2045.Diabetes-induced myocardial injury is a major complication of diabetes.The pathogenesis of myocardial injury induced by diabetic hyperglycemia is complex and involves cardiomyocyte hypertrophy,apoptosis,oxidative stress,inflammatory response,and focal myocardial fibrosis.Unfortunately,there is currently a lack of effective therapeutic drugs for this disease.Therefore,it is crucial to explore novel therapeutic drugs with multiple effects that can target the complex and diverse mechanisms involved in diabetic hyperglycemia-induced myocardial injury.Resveratrol,a common polyphenol found in various traditional Chinese herbs and edible plants such as polygonum cuspidatum,grape,and soybean,has been used as a health food or nutritional supplement.Resveratrol has demonstrated a wide range of pharmacological effects,including cardioprotection and hypoglycemic effects.Although a few studies have reported the protective effect of resveratrol against myocardial injury induced by diabetic hyperglycemia,the specific mechanism remains unclear.Therefore,this study aims to investigate the effect of resveratrol on the rat model of diabetic hyperglycemia-induced myocardial injury,elucidate its mechanism of action,and provide basic theoretical evidence for the potential application of resveratrol in the treatment of diabetic myocardial injury.MethodsIn vivo experiment:A rat model of diabetic hyperglycemia-induced myocardial injury was established by a high-fat diet combined with Streptozotocin(STZ).Resveratrol(with dosages of 100 mg/kg,20 mg/kg)was administered continuously for 8 weeks.The rats’ general physical signs(including hair,body weight,activity level,water intake,food intake),blood glucose level,heart weight,cardiomyopathy indicators,and pathological morphology of myocardial tissue(using HE and immunohistochemical staining)were monitored throughout the experiment,and the pharmacodynamics of resveratrol on diabetic hyperglycemia-induced myocardial injury in rats were evaluated.The effects of resveratrol on apoptotic protein,fibrosis,inflammation and myocardial hypertrophy markers were detected using immunohistochemistry,si-RNA,Western Blot(WB)and RT-PCR.The expression of resveratrol on RAGE,NF-κB and TGF-β1/Smad signaling pathway,as well as the mechanism of its downstream related cytokines,were also investigated.In vitro experiment:H9c2 cardiomyocytes were incubated with high glucose(25mM)to induce an in vitro model of myocardial injury.The effects of resveratrol(at concentrations of 20μg/mL,40μg/mL)on hypertrophy,apoptosis,inflammation and fibrosis of H9c2 cardiomyocytes were validated using immunofluorescence,flow cytometry,WB and RT-PCR.RAGE-specific inhibitors FPS-ZM1 and si-RNA were used to demonstrate the mechanism of RAGE and its downstream NF-κB and TGF-β1/Smad signaling pathways in the protection of resveratrol against hyperglycemia-induced myocardial injury.ResultsIn vivo experiment:Following resveratrol administration,rats with myocardial injury induced by diabetic hyperglycemia exhibited significant improvements in general physical signs,including improved hair color,increased activity levels,and greater water and food intake.Additionally,resveratrol was found to attenuate weight loss of these rats,lower blood sugar levels,alleviate pathological injury in myocardial tissue,reduce cardiomyocyte apoptosis and myocardial hypertrophy,inhibit the expression of inflammatory factors,and suppress activation of RAGE/NF-κB and TGF-β1/Smad signaling pathways.In vitro experiment:Resveratrol at concentrations of ≤50μg/mL did not exhibit significant cytotoxicity or stimulating effect on H9c2 cells.Furthermore,resveratrol administration resulted in alleviating hyperglycemia-induced cardiomyocyte hypertrophy,inhibiting cardiomyocyte apoptosis induced by hyperglycemia,reducing production of inflammatory cytokines stimulated by hyperglycemia,attenuating cardiomyocyte fibrosis induced by hyperglycemia,and inhibiting the RAGE and NF-κB pathway.Additionally,resveratrol was found to inhibit hyperglycemia-induced activation of NF-κB and TGF-β1/Smad3 pathways in a RAGE-dependent manner.ConclusionResveratrol demonstrated a significant protective effect on the rat model of myocardial injury induced by diabetic hyperglycemia.Resveratrol exhibited inhibitory effects on various pathological mechanisms of myocardial injury induced by diabetic hyperglycemia,including anti-inflammatory,anti-fibrosis,anti-hypertrophy,and anti-apoptosis.Resveratrol selectively targeted RAGE and inhibited the activation of NF-κB and TGF-β1/Smad3 signaling pathways induced by hyperglycemia in RAGE.These findings suggest that resveratrol has therapeutic potential in the treatment of myocardial injury induced by diabetic hyperglycemia.