Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species
Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species
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DOI：
10.1182/blood-2004-02-0665
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发表时间：
2004-10-15
期刊：
影响因子：
20.3
通讯作者：
Cook-Mills, JM
中科院分区：
文献类型：
--
作者：
Deem, TL;Cook-Mills, JM
在内皮细胞连接处结合的淋巴细胞在几分钟内外渗。淋巴细胞-内皮细胞结合由受体如血管细胞粘附分子1（VCAM-1）介导。VCAM-1在几分钟内激活内皮细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶，这种活性是VCAM-1依赖性淋巴细胞迁移所必需的。在这份报告中，我们研究了VCAM-1依赖的淋巴细胞迁移过程中基质金属蛋白酶（MMPs）的激活机制。与VCAM-1结合的淋巴细胞迅速激活内皮细胞相关的MMPs。此外，抑制内皮细胞上的MMPs而不是淋巴细胞上的MMPs阻断了VCAM-1依赖的淋巴细胞跨内皮细胞的迁移。内皮细胞MMPs的激活需要VCAM-1刺激的内皮细胞NADPH氧化酶活性，如通过清除活性氧（ROS）和通过NADPH氧化酶的药理学或反义抑制所确定的。外源性添加1 μ M H2O2，VCAM-1刺激内皮细胞产生的H2O2水平，迅速激活内皮细胞相关的MMPs。与此相反，淋巴细胞相关的MMPs的激活被延迟数小时后，结合到VCAM-1，这种激活被阻断抑制内皮细胞ROS的产生。H2O2诱导的淋巴细胞相关金属蛋白酶组织抑制剂（TIMP）减少也有延迟，导致MMP/TIMP比值增加。总之，这是第一个报告的机制，活性氧功能的VCAM-1激活内皮细胞基质金属蛋白酶在VCAM-1依赖性淋巴细胞迁移。(C)2004年，美国血液学会。
Lymphocytes bound at endothelial cell junctions extravasate within minutes. Lymphocyte-endothelial cell binding is mediated by receptors such as vascular cell adhesion molecule 1 (VCAM-1). VCAM-1 activates endothelial cell nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in minutes, and this activity is required for VCAM-1-dependent lymphocyte migration. In this report, we examined mechanisms for activation of matrix metalloproteinases (MMPs) during VCAM-1-dependent lymphocyte migration. Lymphocyte binding to VCAM-1 rapidly activated endothelial cell-associated MMPs. Furthermore, inhibition of MMPs on the endothelial cells but not on the lymphocytes blocked VCAM-1-dependent lymphocyte migration across endothelial cells. The activation of endothelial cell MMPs required VCAM-1-stimulated endothelial cell NADPH oxidase activity as determined by scavenging of reactive oxygen species (ROS) and by pharmacologic or antisense inhibition of NADPH oxidase. Exogenous addition of 1 muM H2O2, the level of H2O2 generated by VCAM-1-stimulated endothelial cells, rapidly activated endothelial cell-associated MMPs. In contrast, activation of lymphocyte-associated MMPs was delayed by hours after binding to VCAM-1, and this activation was blocked by inhibition of endothelial cell ROS generation. There was also a delay in H2O2-induced decrease in lymphocyte-associated tissue inhibitors of metalloproteinases (TIMPs), resulting in an increase in MMP/TIMP ratio. In summary, this is the first report of a mechanism for ROS function in VCAM-1 activation of endothelial cell MMPs during VCAM-1-dependent lymphocyte migration. (C) 2004 by The American Society of Hematology.