Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat
Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat
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DOI：
10.1016/s0008-6363(00)00029-8
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发表时间：
2000-05-01
影响因子：
10.8
通讯作者：
Bryant, JW
中科院分区：
文献类型：
--
作者：
Peterson, JT;Li, H;Bryant, JW
目的：表征大鼠心肌梗死（MI）后左心室（LV）重构期间基质金属蛋白酶（MMP-1、-2、-3、-7、-9、-11、-12、-13和-14）和MMP的内源性组织抑制剂（TIMP-1、-2、-3和-4）上调的时程。方法：结扎雄性大鼠左冠状动脉降支，建立心肌梗死模型。从MI后第1天至第16周评估左室功能和扩张。在同时含有瘢痕和心肌的LV样品上进行蛋白质和mRNA提取。明胶酶活力测定采用酶谱法。对已知在大鼠中切割纤维状胶原的MMP（MMP-8、-13和-14）以及TIMP-1、-2和-4进行Western印迹。结果：平均梗死面积为38.6 ± 1.1%，并产生LV功能障碍和进行性LV扩张。胸腹水，充血性心力衰竭（HF）的标志物，并没有出现，直到12周后MI。在HF进展过程中的不同时间点检测到MMP-2、-8、-9、-13和-14和TIMP-1和TIMP-2的上调。MMP蛋白水平的增加有时在mRNA水平没有相应的升高的情况下发生，TIMP mRNA水平增加而蛋白水平没有增加。MMP-13活性形式在MI后的前2周内升高，而TIMP-1和TIMP-2蛋白水平直到MI后6周才显著升高。MMP-8和MMP-14蛋白水平在心力衰竭进展过程中增加。结论：MMP/TIMP在大鼠左室梗死后随时间推移而上调。一些MMPs在MI后第一周显著升高（MMP-13、-2和-9），另一个直到MI后16周才升高（MMP-14）。LV MMP/TIMP mRNA和蛋白水平之间的解离表明，翻译后加工发生在大鼠心脏。(C)2000 Elsevier Science B. V.保留所有权利。
Objective: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2, -3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP-1, -2, -3, and -4) upregulation during left Ventricular (LV) remodeling following myocardial infarction (MI) in rats. Methods: The descending left coronary artery of male rats (Rattus norvegicus) was ligated to produce a MI. LV function and dilation were assessed from I day to 16 weeks post-MI. Protein and mRNA extraction was done on LV samples containing scar and myocardium together. Gelatinase activity was measured by zymography. Westerns were run on the MMPs known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as TIMP-1, -2, and -4. Results: Average infarct size was 38.6+/-1.1%, and produced LV dysfunction and progressive LV dilation. Thoracic ascites, a marker of congestive heart failure (HF), was not present until 12 weeks post-MI. Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at different timepoints during HF progression. Increased MMP protein levels occurred sometimes without a corresponding elevation in mRNA levels, and increased TIMP mRNA levels without increased protein levels. MMP-13 active form was elevated during the first 2 weeks post-MI while TIMP-1 and TIMP-2, protein levels were not significantly elevated until weeks post-MI. MMP-8 and MMP-14 protein levels increased later during heart failure progression. Conclusion: MMP/TIMP upregulation evolves over time following infarction in the rat LV. Some MMPs were significantly elevated during the first week post-MI (MMP-13, -2, and -9) and another was not until 16 weeks post-MI (MMP-14). The dissociation between LV MMP/TIMP mRNA and protein levels shows that post-translation processing occurs in the rat heart. (C) 2000 Elsevier Science B.V. All rights reserved.