Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1)
Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1)
复制标题
DOI：
10.1182/blood-2003-09-3275
复制
发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Salmi, M
中科院分区：
文献类型：
--
作者：
Koskinen, K;Vainio, PJ;Salmi, M
多形核白细胞（PMNs）通过黏附分子与血管内皮细胞结合，从血液中迁移到炎症区域。血管粘附蛋白1 （Vascular adhesion protein-1, VAP-1）是介导白细胞与内皮细胞相互作用的分子之一。它也是一种内皮细胞表面酶（胺氧化酶），在催化反应中产生活性氧。为了研究VAP-1酶活性在PMN外渗中的作用，我们在几种血流依赖模型中使用了酶活性失活的VAP-1突变体、特异性胺氧化酶抑制剂（包括一种新的小分子化合物）和抗VAP-1抗体。酶抑制剂在层状剪切应力条件下减少PMN在人内皮细胞上的滚动和转运。值得注意的是，酶失活点突变破坏了VAP-1介导转运的能力。此外，在动物炎症模型中，新的VAP-1抑制剂有效地阻止了pmn的外渗。这些数据表明，VAP-1的氧化酶活性控制着PMN在相对不为人所知的转运步骤中从血液中退出。(C) 2004年由美国血液病学会出版。
Polymorphonuclear leukocytes (PMNs) migrate from the blood into areas of inflammation by binding to the endothelial cells of blood vessels via adhesion molecules. Vascular adhesion protein-1 (VAP-1) is one of the molecules mediating leukocyte-endothelial cell interactions. It is also an endothelial cell-surface enzyme (amine oxidase) that produces reactive oxygen species during the catalytic reaction. To study the role of the enzymatic activity of VAP-1 in PMN extravasation, we used an enzymatically inactive VAP-1 mutant, specific amine oxidase inhibitors (including a novel small molecule compound), and anti-VAP-1 antibodies in several flow-dependent models. The enzyme inhibitors diminished PMN rolling on and transmigration through human endothelial cells under conditions of laminar shear stress in vitro. Notably, the enzyme inactivating point mutation abolished the capacity of VAP-1 to mediate transmigration. Moreover, the new VAP-1 inhibitor effectively prevented the extravasation of PMNs in an animal model of inflammation. These data show that the oxidase activity of VAP-1 controls PMN exit from the blood during the relatively poorly understood transmigration step. (C) 2004 by The American Society of Hematology.