Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques - Evidence for activation by proinflammatory mediators
Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques - Evidence for activation by proinflammatory mediators
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DOI：
10.1161/01.cir.99.24.3103
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发表时间：
1999-06-22
期刊：
影响因子：
37.8
通讯作者：
Shah, PK
中科院分区：
文献类型：
--
作者：
Rajavashisth, TB;Xu, XP;Shah, PK
基质金属蛋白酶（MMPs）在动脉粥样硬化斑块中表达，其活性形式可能有助于血管重塑和斑块破坏。在这项研究中，我们验证了膜1型MMP （MT1-MMP）的假设，即膜1型MMP （MT1-MMP）是一种激活前MMP-2（明胶酶a）的新型跨膜MMP，在人类动脉粥样硬化斑块中表达，其表达受促炎分子调节。方法和结果：用免疫细胞化学方法检测正常和动脉粥样硬化人动脉中MT1-MMP的表达。在组织培养中维持的人隐静脉源性平滑肌细胞（SMCs）中，MT1-MMP的表达在基础条件下和对促炎分子（白细胞介素[IL]-1 α、肿瘤坏死因子[TNF]- α和氧化LDL [ox-LDL]）的反应中进行了检测，方法是使用Northern blot和核糖核酸酶保护法检测mRNA， Western blot和免疫沉淀法检测蛋白质，明胶酶谱法检测催化活性。正常血管壁内侧的SMCs表达MT1-MMP，在动脉粥样硬化动脉中，MT1-MMP在与SMCs和巨噬细胞（M phi）共定位的复杂动脉粥样硬化中表达。培养的SMCs组成性地表达MT1-MMP mRNA和蛋白质，在暴露于IL-1 α、tnf - α和ox-LDL（硫代巴比妥酸反应物质，13.4 nmol/mg LDL蛋白）的4至8小时内，MT1-MMP mRNA和蛋白质以时间依赖性的方式比对照组增加2至4倍，而天然LDL则没有影响。流式细胞术显示，在暴露于10 ng/mL tnf - α后6小时内，人单核细胞来源的M - phi的MT1-MMP表达比基线增加3.8倍。结论：本研究表明，在人动脉粥样硬化斑块中，SMCs和mphi表达MT1-MMP，促mmp -2的激活剂。此外，促炎分子上调血管SMCs和mphi中MT1-MMP的表达。因此，促炎分子激活SMCs和mphi可能通过调节MT1-MMP的表达影响动脉粥样硬化的细胞外基质重塑。
Background-Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.Methods and Results--MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1 alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP, In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (M phi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1 alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived M phi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.Conclusions-This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and M phi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and M phi. Thus, activation of SMCs and M phi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.