The Effect Of Valsartan And Fluvastatin On The Connective Tissue Growth Factor Expression In Experimental Diabetic Cardiomyopathy

Many human and animal studies have suggested the existence of diabetic cardiomyopathy(DCM),which has been defined as ventricular dysfunction that occurs independently of macrovascular and coronary artery disease.The early cardiac alterations of DCM are left ventricular(LV)hypertrophy and diastolic dysfunction.In well-controlled subjects with type 2 diabetes without clinically apparent chronic complications,Poirier et al reported a prevalence of LV diastolic dysfunction of up to 60%.About 10%to 30%patients with diabetes developed heart failure.DCM is characterized by cadiomyocyte hyperplasia and hypertrophy,accumulation of extracellular matrix(ECM)and interstitial fibrosis.The underlying molecular and pathophysiological mechanisms of DCM are incompletely understood,which need to be further investigated. Objective:The present study examined the effect of abnormal expression of connective tissue growth factor(CTGF)on cardiac interstitial fibrosis and heart failure in streptozotocin (STZ)-induced diabetic rats,in order to explore the effect of valsartan and fluvastatin on preventing the development of DCM and possible mechanisms.Method:Diabetes was induced in male Sprague-Dawley(SD)rats by theⅣinjection of streptozotocin(STZ).The diabetic rats were randomly assigned to receive valsartan (30mg.kg^-1·d^-1),fluvastatin(4mg·kg^-1·d^-1),both of these two drugs or nothing.Each group had eight rats.Another eight rats were used as non-diabetic controls.Fasting plasma glucose(FBG),triglyceride(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C)and glycated hemoglobin(HbAlc)were measured 12 weeks after randomization.Left ventricular systolic pressure(LVSP),left ventricular end-diastolic pressure(LVEDP),the maximal value of the first derivative of the pressure(±dp/dt max)of left ventricle were recorded with a catheter.Hearts of rats were obtained after catheterization for determination of heart weight/body weight(HW/BW)ratio.The histopathological alterations of myocardium of LV free wall were studied by HE,PAS and Van-Gieson(VG)staining. CTGF gene expression was assessed by semi-quantitative real-time RT-PCR.Western blot was used to detect the levels of cardiac collagen typeⅠandⅢ,transforming growth factor-β1(TGF-β1)and CTGF protein. Result:1,Compared with the control group,diabetic rats displayed more metabolic disorders with lower body weight and higher HW/BW ratio(P＜0.01). Valsartan,fluvastatin and the combination could reduce the HW/BW ratio by 10%,8%and 13%respectively(P＜0.01).The levels of FBG,HbAlc, TG,TC,and LDL-C were significantly higher in diabetic rats(P＜0.01). Fluvastatin and the combination therapy could reduce the TC and LDL-C (P＜0.01).2,The diabetic rats showed a significant reduction of LVSP and±dp/dt_max, and an elevation of LVEDP(P＜0.05).Hemodynamic parameters in the treated groups improved significantly(P＜0.05).Combination therapy was better than mono-therapy(P＜0.05).3,More collagen fibers were observed by the VG staining in the diabetic rats (P＜0.05).Valsartan and fluvastatin could reduced the collagen accumulation(P＜0.05).There was no significant difference between the combined and mono-therapy.4,Compared to the non-diabetic controls,Significant upregulation of CTGF mRNA was detected in diabetic ones(P＜0.05).Valsartan and Fluvastatin reduced basal CTGF gene expression in the diabetic rats by 20%and 28% respectively.The combination therapy resulted in a further reduction of 35%(P＜0.05).5,TGF-β1 and CTGF protein expression increased in the diabetic myocardium compared with the non-diabetic rats.Collagen typeⅠandⅢ, which were considered to be major components of ECM,also increased in the diabetic myocardium(P＜0.01).All interventions diminished the ECM accumulation and combined therapy performed better than mono-therapy (p＜0.05).Conclusion:1,The over-expression of CTGF mRNA and TGF-β1 contributed to the myocardial fibrosis in diabetic rats and the subsequent LV diastolic dysfunction.2,Valsartan and fluvastatin could suppress the expression of CTGF and TGF-β1,which could reduce the production of Collagen typeⅠandⅢand the myocardial fibrosis.Combination of the two drugs could preserve the cardiac function in diabetic cardiomyopathy.