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ADAMTS-7，血管重塑中的新靶点

王利, 王宪, 孔炜^*

北京大学基础医学院生理与病理生理学系，分子心血管教育部重点实验室，北京 100191

摘要

血管重塑是动脉粥样硬化和血管再狭窄发病中的一个重要的病理生理学过程。越来越多的证据表明，具有降解细胞外基质能力的酶在血管重塑中发挥着重要的作用。含I 型血小板反应蛋白的解聚素和金属蛋白酶(a disintegrin and metalloproteinasewith thrombospondin motifs, ADAMTS)家族是一类最近被克隆的金属蛋白酶家族，该家族成员同样具备降解细胞外基质的能力。ADAMTS 家族由19 个家族成员组成，参与了一系列的正常生理学功能，如发育、血管新生和凝血等。而ADAMTS家族成员的异常表达通常会引发各种疾病，如关节炎、肿瘤、凝血功能障碍性紫癜。本文从ADAMTS 家族第七个成员——ADAMTS-7 的结构、组织分布、调控、尤其是通过其底物软骨寡聚基质蛋白(cartilage oligomeric matrix protein, COMP)精细调控血管稳态几个方面综述了其在血管重塑中作用的最新研究进展。

关键词： ADAMT S-7 ; 软骨寡聚基质蛋白; 血管平滑肌; 迁移; 增殖

分类号：R331.3+2

ADAMTS-7, a novel proteolytic culprit in vascular remodeling

Wang Li, WANG Xian, KONG Wei^*

Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Beijing 100191, China

Abstract

Vascular remodeling is being recognized as a fundamental process during atherosclerosis and restenosis. Cumulative studieshave demonstrated that extracellular matrix (ECM) degrading enzymes play a critical role during vascular remodeling. A disintegrin andmetalloproteinase with thrombospondin motifs (ADAMTS) family is a recently identified metalloproteinase family which also hascapacity to degrade ECM. ADAMTS family consists of 19 members and has been linked to a variety of physiological processesincluding development, angiogenesis, coagulation etc. Aberrant expression or function of ADAMTS members have been implicated tomany disease states such as arthritis, cancer, thrombocytopenic purpura, but barely described with regard to cardiovascular disease.This review summarizes the recent advance with respect to the role of ADAMTS-7 in vascular remodeling. We review the structure,tissue distribution, substrate, expression and regulation of ADAMTS-7, especially highlight the fine tune by ADAMTS-7 of itssubstrate cartilage oligomeric matrix protein (COMP) in maintaining vascular homeostasis. By use of rat carotid artery balloon injurymodel to mimic vascular injury in vivo, we found that ADAMTS-7 protein was accumulated preferentially in neointima and mainlylocalized in vascular smooth muscle cells (VSMCs). Adenovirus-elicited ADAMTS-7 overexpression greatly accelerated VSMCsmigration and proliferation both in vivo and in vitro, and subsequently aggravated neointima thickening post-injury. Conversely,siRNA-mediated ADAMTS-7 knock down bona fide inhibited VSMCs migration and proliferation in cultured VSMCs and injuredarteries, and ultimately ameliorated neointima area. Further studies demonstrated that ADAMTS-7 facilitated VSMCs migrationthrough degradation of its substrate COMP. Moreover, we elucidated that COMP has the capacity to maintain the contractilephenotype of VSMCs through interacting with integrin α7β1. ADAMTS-7 may therefore serve as a novel therapeutic target foratherosclerosis and postangioplasty restenosis.

Key words: ADAMTS-7; COMP; vascular smooth muscle; migration; proliferation

收稿日期：2010-06-08　　录用日期：2010-07-23

通讯作者：孔炜　　E-mail: kongw@bjmu.edu.cn

引用本文：

王利, 王宪, 孔炜. ADAMTS-7，血管重塑中的新靶点[J]. 生理学报 2010; 62 (4): 285-294.

Wang Li, WANG Xian, KONG Wei. ADAMTS-7, a novel proteolytic culprit in vascular remodeling. Acta Physiol Sin 2010; 62 (4): 285-294 (in Chinese with English abstract).