组织激肽释放酶特异性抑制剂激肽抑制蛋白在血管重塑中的新作用。

Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling.

作者信息

Chao J, Miao R Q, Chen V, Chen L M, Chao L

机构信息

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.

出版信息

Biol Chem. 2001 Jan;382(1):15-21. doi: 10.1515/BC.2001.003.

DOI:10.1515/BC.2001.003

PMID:11258665

Abstract

We have purified, cloned and characterized kallistatin, a tissue kallikrein-binding protein (KBP) in humans and rodents. Kallistatin is a unique serine proteinase inhibitor (serpin) with Phe-Phe residues at the P2 and P1 positions. Structural and functional analysis of kallistatin by site-directed mutagenesis and protein engineering indicate that wild-type kallistatin is selective for tissue kallikrein. Kallistatin is expressed and localized in endothelial and smooth muscle cells of blood vessels and has multiple roles in vascular function independent of the tissue kallikrein-kinin system. First, kallistatin induces vasorelaxation of isolated aortic rings and reduces renal perfusion pressure in isolated rat kidneys. Transgenic mice overexpressing rat kallistatin are hypotensive, and adenovirus-mediated gene delivery of human kallistatin attenuates blood pressure rise in spontaneously hypertensive rats. Second, kallistatin stimulates the proliferation and migration of vascular smooth muscle cells in vitro and neointima formation in balloon-injured rat arteries. Third, kallistatin inhibits the proliferation, migration and adhesion of endothelial cells in vitro and angiogenesis in the rat model of hindlimb ischemia. These results demonstrate novel roles of kallistatin in blood pressure regulation and vascular remodeling.

摘要

我们已经纯化、克隆并鉴定了人及啮齿动物体内的一种组织激肽释放酶结合蛋白（KBP）——激肽抑制蛋白。激肽抑制蛋白是一种独特的丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂家族），在P2和P1位置具有苯丙氨酸 - 苯丙氨酸残基。通过定点诱变和蛋白质工程对激肽抑制蛋白进行的结构和功能分析表明，野生型激肽抑制蛋白对组织激肽释放酶具有选择性。激肽抑制蛋白在血管内皮细胞和平滑肌细胞中表达并定位，在血管功能中具有多种作用，独立于组织激肽释放酶 - 激肽系统。首先，激肽抑制蛋白可诱导离体主动脉环的血管舒张，并降低离体大鼠肾脏的肾灌注压。过表达大鼠激肽抑制蛋白的转基因小鼠血压降低，腺病毒介导的人激肽抑制蛋白基因递送可减轻自发性高血压大鼠的血压升高。其次，激肽抑制蛋白在体外刺激血管平滑肌细胞的增殖和迁移以及球囊损伤大鼠动脉中的新生内膜形成。第三，激肽抑制蛋白在体外抑制内皮细胞的增殖、迁移和黏附以及后肢缺血大鼠模型中的血管生成。这些结果证明了激肽抑制蛋白在血压调节和血管重塑中的新作用。