厄贝沙坦对糖尿病大鼠心肌纤维化中基质金属蛋白酶通路及相关因子的影响

Effect of irbesartan on matrix metalloproteinase pathway related factors in diabetes induced myocardial fibrosis in rat model

目的观察厄贝沙坦是否对抗糖尿病大鼠心肌纤维化,探讨其对基质金属蛋白酶(MMPs)通路相关因子的影响。方法 30只雄性SD大鼠随机分为对照(Con)组、糖尿病(DM)组、厄贝沙坦+糖尿病组(Ir+DM),每组10只。高糖髙脂饮食12周后,Masson染色观察心肌组织纤维化改变。ELISA测定心肌组织Ⅰ型胶原(ColⅠ)、Ⅲ型胶原(ColⅢ)、基质金属蛋白酶组织抑制因子1(TIMP-1)、组织抑制因子2(TIMP-2)含量及基质金属蛋白酶2(MMP-2)、MMP-9、MMP-14蛋白表达。结果与Con组比较,DM组FBG增加,心体比增大,心肌胶原纤维粗大,部分胶原沉积,ColⅠ、ColⅢ、TIMP-1、TIMP-2含量升高[(133.80±6.24)vs(262.07±9.84),(33.80±2.34)vs(71.42±2.59),(10.64±1.04)vs(38.05±1.29),(7.79±0.48)vs(23.15±0.82)ng/mg,P<0.01],MMP-2、MMP-9蛋白表达降低[(1.60±0.10)vs(0.80±0.05),(0.51±0.03)vs(0.26±0.01)ng/mg,P<0.01],MMP-14蛋白表达增加[(1.01±0.06)vs(1.49±0.05),P<0.01]。与DM组比较,厄贝沙坦干预改善心肌组织纤维化,ColⅠ、ColⅢ含量减少,TIMP-1、TIMP-2水平降低[(262.07±9.84)vs(167.12±7.88),(71.42±2.59)vs(43.23±2.30),(38.05±1.29)vs(15.66±1.42),(23.15±0.82)vs(11.01±0.90)ng/mg,P<0.01],MMP-2、MMP-9蛋白表达增加[(0.80±0.05)vs(1.30±0.05),(0.26±0.01)vs(0.43±0.02),P<0.01],MMP-14蛋白表达降低[(1.49±0.05)vs(1.07±0.05),P<0.01]。结论糖尿病可诱导心肌纤维化,厄贝沙坦通过调节MMPs信号通路及相关因子减轻纤维化程度。

Objective To explore the role of matrix metalloproteinase（MMPs）pathway related factors in the process of myocardial fibrosis in diabetic rat model and to investigate the protection mechanism of irbesartan. Methods All male SD rats were randomly divided into three groups：control（Con）,diabetes mellitus（DM）and irbesartan＋diabetes mellitus（Ir＋DM）.After 12 weeks of high-sugar and high-fat diet,the myocardial morphological and fibrotic changes were observed by Masson staining.The contents of ColⅠ,Col Ⅲ,TIMP-1 and TIMP-2 were evaluated by ELISA method.The protein expressions of MMP-2、MMP-9 and MMP-14 were analyzed by Western blot. Results Compared with Con group,in DM group,FBG and H/R levels were increased,myocardial fiber became hyperplasia and collagen deposited.The contents of ColⅠ,Col Ⅲ,TIMP-1 and TIMP-2 in diabetic myocardium were higher than that in Con group[（133.80±6.24）vs（262.07±9.84）,（33.80±2.34）vs（71.42±2.59）,（10.64±1.04）vs（38.05±1.29）,（7.79±0.48）vs（23.15±0.82）ng/mg,respectively,P〈0.01].The protein expressions of MMP-2 and MMP-9 were decreased [（1.60±0.10）vs（0.80±0.05）,（0.51±0.03）vs（0.26±0.01）,P〈0.01].MMP-14 protein expression was increased[（1.01±0.06）vs（1.49±0.05）,P〈0.01].Irbesartan intervention improved diabetic cardiac fibrosis.Compared with DM group,in Ir＋DM group,the contents of ColⅠ,ColⅢ,TIMP-1 and TIMP-2 were decreased [（262.07±9.84）vs（167.12±7.88）,（71.42±2.59）vs（43.23±2.30）,（38.05±1.29）vs（15.66±1.42）,（23.15±0.82）vs（11.01±0.90）ng/mg,P〈0.01]as well as the protein expression of MMP-14[（1.49±0.05）vs（1.07±0.05）,P〈0.01],while the protein expression of MMP-2,MMP-9 were increased[（0.80±0.05）vs（1.30±0.05）,（0.26±0.01）vs（0.43±0.02）,P〈0.01]. Conclusion Irbesartan may improve myocardial fibrosis in diabetic rats by MMPs pathway related factors.