贝那普利对糖尿病大鼠心肌细胞外基质重塑中基质金属蛋白酶及转化生长因子表达的影响

目的研究贝那普利对糖尿病大鼠心肌基质重塑的作用机制。方法 SD大鼠ip注射链脲佐菌素制备糖尿病模型。治疗组ig给予BZ 10 mg.kg-1,连续12周。光镜及电镜下观察左心室心肌组织改变,测定心脏质量指数;Western印迹法测定左心室心肌组织胶原Ⅰ型及Ⅲ型含量,基质金属蛋白酶2(MMP-2),金属蛋白酶组织抑制因子2(TIMP-2)表达及转化生子因子β1(TGF-β1)和结缔组织生长因子(CTGF)表达的变化。结果与正常对照组相比,糖尿病组大鼠心脏质量指数明显升高,胶原Ⅰ型及Ⅲ型表达明显增加(P<0.05),MMP-2表达减少、TIMP-2表达增加(P<0.01),TGF-β1和CTGF表达明显增强(P<0.05),心肌间质纤维增生。大鼠连续ig给予贝那普利12周后,心脏质量指数明显降低〔(4.13±0.18)vs(3.42±0.13)mg.g-1〕;胶原Ⅰ型及Ⅲ型表达明显减少(P<0.05),MMP-2表达增加,TIMP-2表达减少(P<0.05),TGF-β1及CTGF表达明显减弱(P<0.05),心肌间质纤维增生减轻。与正常对照组相比,贝那普利组大鼠心肌MMP-2表达减少,TIMP-2及CTGF表达仍增加。结论贝那普利可能通过抑制糖尿病大鼠心肌组织TGF-β1和CTGF表达以及增强基质金属蛋白酶表达,从而抑制糖尿病心肌间质纤维化,改善心肌细胞外基质重塑。

Effects of benazepril on expression of matrix metalloproteinase and transforming growth factors in myocardial extracellular matrix remodeling of diabetic rats

OBJECTIVE To study the mechanism of benazepril(BZ) on myocardial extracellular matrix remodeling of diabetic rats. METHODS Diabetic animal models were induced by injecting streptozotocin into Spraque-Dawley rats. BZ 10 mg·kg^-1 was ip given to rats in BZ group, once daily, for 12 weeks. The left ventricular myocardium was observed with the light microscope and electronmicroscope. Heart mass indexes were detected. Collagen typeⅠ and typeⅢ, matrix metalloproteinases (MMP- 2), tissue inhibitor of metalloproteinases (TIMP- 2), transforming growth factor-β₁ (TGF-β₁) and connective tissue growth factor (CTGF) were detected by Western blotting. RESULTS Compared with normal control group, the heart mass indexes and the expression of collagen typeⅠ and typeⅢ were higher in diabetes group（P＜0.05）. TIMP- 2 protein in diabetes group were significantly higher while the expression of MMP-2 was significantly lower（P＜0.01）. The expression of TGF-β₁ and CTGF was obviously strengthened（P＜0.05）. Myocardial interstitial fibrosis occurred in diabetic rats. After benazepril was used for 12 weeks, compared with diabetes group, the heart mass indexes obviously decreased from (4.13±0.18)mg·g^-1 to (3.42±0.13)mg·g^-1. The expression of collagen typeⅠ and typeⅢ was lower（P＜0.05）. The expression of MMP- 2 increased, the expression TIMP-2 decreased（P＜0.05）, and the expression of TGF-β₁ and CTGF was degraded significantly（P＜0.05）. Myocardial interstitial fibrosis was also lessened. Compared with normal control group, MMP-2 expression decreased, but the expression of TIMP- 2 and CTGF still increased in BZ group. CONCLUSION BZ could inhibit the myocardial interstitial fibrosis of diabetic rats, improve myocardial extracellular matrix remodeling by inhibiting of TGF-β₁ and CTGF expression and upregulating MMP-2 expression.