肿瘤坏死因子α在大鼠心肌梗死后心肌间质重塑和心力衰竭中的作用

Role of Tumor Necrosis Factor-α in Postmyocardial Infarction Extracellular Matrix

目的 :探讨心肌梗死后大鼠心肌肿瘤坏死因子α表达、基质金属蛋白酶 (MMPs)及基质金属蛋白酶组织抑制剂(TIMPs)变化与心肌胶原代谢和心功能改变之间的相互联系。方法 :结扎大鼠冠状动脉前降支复制心肌梗死模型 ,为心肌梗死组。同时设假手术组 ,分别于术后 4周、8周、12周行血流动力学检测 ,称取心脏组织湿重。对非梗死区心肌组织采用逆转录—多聚酶链反应 (RT PCR)法检测肿瘤坏死因子α信使核糖核酸 (mRNA)表达 ,Western blot法检测中性粒细胞胶原酶 (MMP 8)、明胶酶 (MMP 9)及TIMP 1蛋白表达 ,明胶酶谱法检测明胶分解活性和天狼猩红染色偏振光下检测心肌胶原含量。结果 :①心肌梗死组较同期假手术组左心室舒张末压均显著增加 (P <0 .0 5 ) ,平均动脉压、左心室内压最大上升和下降速率则显著降低 ,有极显著性差异 (P <0 .0 1) ;除 12周组左心室相对重量外 ,其余时相左心室相对重量和右心室相对重量均显著增加 (P <0 .0 5 )。②心肌梗死组不同时相心肌较同期假手术组肿瘤坏死因子αmRNA显著增加 ,呈时间依赖性 ;MMP 8、MMP 9蛋白表达及MMP明胶酶分解活性均较同期假手术组明显增加 ,而TIMP 1差异无显著性 (P >0 0 5 ) ;心肌胶原含量增加 ,与心功能呈负相关。结论 :肿瘤坏死因子α基因过度表达与MMPs蛋白?

Objective:To investigate the effect of tumor necrosis factor-α(TNF-α)mRNA expression on postmyocardial infarction extracellular matrix(ECM) remodeling in rats. Methods:Male rats were randomised to proximal left anterior descending coronary artery ligation. The rats were killed at 4, 8, and 12 weeks after ligation to examine gene expression of TNF-α, protein levels of matrix metalloproteinases(MMP-8, MMP-9) and tissue inhibitor of metalloproteinases(TIMP-1), MMP gelatinlytic activity, and collagen volume fraction was assessed histomorphometrically from noninfarcted myocardium. Sham-operated rats were used as the controls. Results:Compared with the sham-operated group, the myocardial infarction rats showed significant decrease in arterial pressure, maximal ascending and descending velocity of the left ventricular pressure(±dp/dt max), and a significant increase in left ventricular end-diastolic pressure(LVEDP) (all p<0.05). As compared with sham-operated rats, except LVW/BW in MI 12w group, LVW/BW and RVW/BW were increased significantly. In comparison with sham-operated group, TNF-α mRNA production was increased significantly, levels of MMP-8 and MMP-9 protein, MMP gelatinlytic activity, and collagen volume fraction (CVF) were significantly increased at 4, 8 and 12 weeks after ligation in noninfarcted myocardium. Conclusions:Myocardial TNF-α mRNA overexpression is consistent with the increased levels of MMPs protein, and MMP gelatinlytic activity. These findings suggest that TNF-α plays an important role in postinfarction extracellular matix remodeling and progressive heart failure.