Expression Of Platelet-derived Growth Factor-B In Myocardium Of Diabetic Rats And The Intervention Of Valsartan

【Objective】To investigate the expression of platelet-derived growth factor-B (PDGF-B)in myocardium of diabetic rats and the intervention of valsartan,and to evaluate the role of PDGF-B in the pathogenesis of diabetic cardiomyopathy.【Methods】The first part:Sixty 8-week-old male Sprague-Dawley(SD)rats were randomized into two groups,the normal control group and diabetic group, thirty rats in each group.Diabetes was induced by streptozotocin(STZ) intraperitoneal injection.Blood glucose and weight of all rats were accessed once two weeks.Six rats were selected at random from the two groups respectively at 4,8,12 weeks of diabetic duration.After rats were killed,the weights of body,whole heart and left ventricle were measured to calculate the ratio of heart weight to body weight(H/B)and the left ventricle mass index(LVMI).The myocardial ultrastructure of the two groups at 12 weeks duration were obserbed by electron microscope, the coronary artery oritices were also observed by light microscope. The mRNA and protein expression of PDGF-B,fibronectin(FN),collagen type Ⅲ(ColⅢ)were compared between the two groups of various duration by RT-PCR and immunohistochemistry methods respectively.The second part:Thirty-two 8-week-old rats were divided into four groups: normal control rats,untreated streptozotocin-induced diabetic rats,diabetic rats treated with small-dose valsartan(10mg/kg/d), large-dose valsartan(30mg/kg/d),eight rats in each group.Rats were killed in 12 weeks after intervention,plasma and cardiac angiotensinⅡ(AngⅡ)of each group were determined by radioimmunoprecipitation assay.Myocardial interstitial and perivascular collagen were analyzed using picrosirus red technique and computer image analysis system.The other experimental methods were similar to the first part.【Results】The first part:In 12 weeks,diabetic rats showed conspicuous myocardial lesions with discruption of myocardial cell,degeneration of mitochondrial,formation of muscle contraction bands,mildly thinkening of myocardial capillary basement membrance,as well as accumulation of interstital and perivascular collagenous fibril.No abnormality was found along the coronary artery oritices.These results indicated the formation of diabetic cardiomyopathy.H/B and LVMI were raised in the diabetic group,which were aggravated with the developemet of diabetes. Notable upregradulation of PDGF-B mRNA and protein coincied with an apparent increase of FN,ColⅢexpression in diabetic myocardium(P＜0.01 respectively).These alterations were enhanced gradually along with longer diabetic duration.PDGF-B had a significant positive correlation with FN and ColⅢ(r=0.766,0.794,P＜0.01 respectively)The second part:After the intervention of valsartan for 12 weeks, plasma and cardiac AngⅡwere significantly elevated,the pathogenic changes of myocardial ultrastructure were improved and fibratic lesions were attenuated in the valsartan treated groups.H/B and LVMI were obviously lowered,the expression of FN and ColⅢin myocardium was decreased,and myocardial interstitial collagen volume fraction (CVF)was also reduced(P＜0.01 respectively).PDGF-B mRNA and protein expression were downregulated in the valsartan treated groups (P＜0.01 respectively).The PDGF-B mRNA expression of diabetic rats treated with small-dose and large-dose valsartan were decreased by 27% and 56%respectively,compared with that of untreated diabetic group.All these effects were dependent on dose.【Conclusions】(1)In STZ-induced diabetic SD rats,diabetic cardiomyopathy presents at 12 weeks of diabetic duration.(2)Upregulation of PDGF-B is stongly correlated with the concomitant accumulation of extracellular matrix(ECM) component.PDGF-B plays an important role in the development of fibrotic lesions,and is involved in the onset and progression of diabetic cardiomyopathy.This perhaps makes PDGF-B become a new appealing target for therapeutic intervention in myocardial fibrosis.(3)Valsartan treatment attenuates ECM accumulation,reduce myocardial fibrosis and ameliorates myocardial structure in diabetic rats.(4)Down-regulating the overexpression of PDGF-B in diabetic is an underlying mechanism of valsartan in the prevention of myocardial fibrosis and cardiac protection.