Expression Of Connective Tissue Growth Factor In Myocardium Of Diabetic Rats And The Intervention Of Fluvastatin

[Objective]To investigate the expression of connective tissue growth factor (CTGF) in myocardium of diabetic rats and the intervention of fluvastatin , and to evaluate the role of CTGF in the pathogenesis of diabetic cardiomyopathy . [Methods]The first part:(1)sixty 8-week-old male Sprague-Dawley (SD) rats were divided into two groups (30 rats in each group) randomly: the normal control group and diabetic group. Diabetes was induced by streptozotocin (STZ) intraperitoneal injection in SD rats of diabetic group . Blood glucose and weight of all rats were accessed once two weeks . (2)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 the whole heart and left ventricle were measured , whice were used to calculate the ratio of heart weight to body weight (H/B) and the left ventricle mass index (LVMI) . (3)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 . (4)The mRNA and protein expression of CTGF, transforming growth factor β₁ , (TGF-β₁) , f ibronectin(FN), collagen type III (ColIII)were compared between the two groups of various duration by RT-PCR and immunohistochemistry methods respectively .The second part: (1)thirty-two 8-week-old male SD rats were divided into the normal control group (8 rats) and the diabetic group (24 rats , induced by STZ intraperitoneal injection) , then the diabetic rats were allocated to 3 groups at random as follow (8 rats in each group) : untreated group (distilled water ig.) , small-dose fluvastatin (7mg/kg/d ig.) , large-dose fluvastatin (20mg/kg/d ig.) . (2)Rats were killed after 12 weeks' intervention, Serum lipids of each groups were determined . (3)The rest experimental methods were similar to the first part . [Results)The first part : (l)In 12 weeks , STZ-induced diabetic SD 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 . (2)H/B and LVMI were raised in the diabetic group , whice were aggravated with the developemet of diabetes . (3) Notable upregradulation of CTGFmRNA and protein coincied with an apparent increase of FN , ColIII expression in diabetic myocardium . These alterations were enhanced gradually along with longer diabetic duration . (4)The expression of TGF- ï¿¡ , was increased in diabetic myocardium . But it appeared an downtrend in 12 weeks of diabetes . (5)The expression of CTGF was positively correlative with that of TGF- P ,. (6)CTGF had a significant positive correlation with FN and ColIII , whice was more obvious than that of TGF- P ,. The second part : (1)After treating rats with fluvastatin for 12weeks, reduction of LDL-C and TC were found. In the group with large-dose fluvastatin treatment, TG was decreased and HDL-C was increased slightly. (2)The pathogenic changes of myocardial ultrastructure were improved and fibratic lesions were attenuated in the fluvastatin treated groups . (3) Fluvastatin treatment obviously decreased the expression of FN and Col III in myocardium of diabetic rats . (4)Downregulation of CTGF and TGF-{3 , was also observed in the fluvastatin treated groups . While the suppression of CTGF was more significant . All these effects were dose dependent way. [Conclusions!(l)In STZ-induced diabetic SD rats , diabetic cardiomyopathy presents at 12 weeks of diabetic duration . (2)Deregulation of CTGF is stongly correlated with the concomitant accumulation of extracellular matrix (ECM) component . CTGF plays an important role in the development of fibrotic lesions , and is involved in the onset and progression of diabetic cardiomyopathy . (3)As a downstream mediator of TGF- 3 , in the course of fibrosis , CTGF is closely linked to TGF- P ,. However , it has more direct and persistent contribution to the formation of diabetic cardiomyopathy . This perhaps makes CTGF become a new appealing target for therapeutic intervention in myocardial fibrosis . (4) In addition to the effective regulation of lipid metabolism , Fluvastatin attenuates ECM accumulation, and ameliorates myocardial structure in diabetic rats . (5)Down-regulating the overexpression of CTGF in diabetic is an underlying mechanism of fluvastatin in the prevention of myocardial fibrosis and cardiac protection .