Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata.
Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata.
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DOI：
10.1161/atvbaha.114.303326
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Libby P
中科院分区：
文献类型：
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作者：
Quillard T;Araújo HA;Franck G;Tesmenitsky Y;Libby P
大量证据表明基质金属蛋白酶家族的间质胶原酶与斑块破裂和致命性血栓形成有关。因此，了解可能影响这些酶表达及其功能的代偿机制具有重要的临床意义。这项研究在小鼠身上评估了两种主要胶原酶对胶原含量和其他斑块特征的未知相对影响。ApoE−/−小鼠、MMP13−/−apoE−/−、MMP8−/−apoE−/−双基因敲除小鼠和MMP13−/−MMP8−/−apoE−/−三基因敲除小鼠分别摄入高胆固醇饲料10周和24周。与载脂蛋白E−/−对照组相比，dko和tko小鼠都显示出类似的动脉粥样硬化病变形成。主动脉根部切片分析表明，MMP8/MMP13缺陷小鼠和MMP13缺陷小鼠的病变组织中纤维胶原的积聚多于载脂蛋白E−/−对照组和MMP8−/−载脂蛋白−/−DKO。我们进一步利用原位酶谱检测MMPs对斑块胶原酶分解的相对影响。单独的基质金属蛋白酶-13缺失可以抑制皮损中的胶原酶活性，这表明基质金属蛋白酶-13在这一过程中起着主要作用。MMP13和MMP13/MMP8缺乏并不改变巨噬细胞的含量，但与平滑肌细胞积聚减少有关。这些结果表明，在小鼠基质金属蛋白酶间质胶原酶中，在动脉粥样硬化中，基质金属蛋白酶-13比基质金属蛋白酶-8在胶原降解中占优势。这些发现为鉴定和选择性靶向一种主要胶原酶提供了理论基础，该胶原酶用于调节被认为在临床并发症中至关重要的斑块结构的关键方面，尽管它们不能直接翻译成人类病变，其中也含有基质金属蛋白酶-1。
Substantial evidence implicates interstitial collagenases of the MMP family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions therefore have important clinical implications. This study assessed in mice the unknown relative impact of the two principal collagenases on collagen content and other plaque characteristics. apoE−/− mice, MMP-13−/− apoE−/−, MMP-8−/− apoE−/− double knockout (DKO) mice, and MMP-13−/− MMP-8−/− apoE−/− triple knockout (TKO) mice consumed a high-cholesterol diet for 10 and 24 weeks. Both DKO and TKO mice showed comparable atherosclerotic lesion formation compared to apoE−/− controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13-deficient and MMP-13-deficient mice accumulate more fibrillar collagen than apoE−/− controls and MMP-8−/− apoE−/− DKO. We further tested the relative impact of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content, but associated with reduced accumulation of smooth-muscle cells. These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.