Abstract 1817: Chronic Treatment with Resveratrol Restores Serca 2a Expression and Improves Cardiac Function of Diabetic Mice

Abstract

Background: Diabetic cardiomyopathy is characterized by impaired cardiac contractility. An important contributor to diastolic dysfunction in the diabetic heart is the reduced activity of sarcoplasmic reticulum calcium pump (SERCA2a). Over expression of SERCA2a alone in transgenic mice protected diabetic hearts from severe contractile dysfunction. Resveratrol (RSV) is a phytoalexin, present in dietary supplements and found naturally in red grape skin and red wine. It shows a multitude of cardio protective effects including anti-hypertrophic, anti-oxidant, anti-ischemic and antiarrythmic. Its role in diabetic cardiomyopathy has not been evaluated. Objectives: We tested the hypothesis that chronic treatment with RSV improves contractile function of the diabetic heart by enhancing SERCA2a expression involving transcriptional regulatory mechanisms. Methods and Results: Adult CD 1 mice were injected with streptozotocin (150 mg / kg i.p.). Mice with more than 400 mg /dL blood glucose levels were considered diabetic, vehicle injected animals served as controls. Half of the diabetic animals were fed RSV enriched diet (0.067%). After three months, by echocardiography diabetic animals showed increased LVESD (38%), increased LVEDD (22%), and reduced fractional shortening (46%). This was accompanied by reduced SERCA2a and SIRT1 protein expression as well as a 3-fold decline in SERCA2a mRNA as assessed by real-time PCR. RSV treatment improved LV function and SERCA2a mRNA to almost normal levels. In primary cultures of cardiomyocytes, transient transfection analysis of SERCA2a promoter / CAT reporter construct (consisting of 1.5 Kb SERCA2a promoter region) revealed a 4-fold decline in SERCA2a promoter activity when cells were grown in high glucose (33 mM) for 5 days as compared to cells grown in normal glucose (5.5 mM) for a comparable period of time. The decline in reporter expression was prevented by pretreatment with RSV ( 0.5 uM). Conclusions and Implications: Our results indicate that in diabetic hearts, resveratrol improves cardiac function by enhancing SERCA2a expression. This effect is mediated at the transcription level possibly involving SIRT1 activiity.