Analysis of the effects of Gla-containing proteins and their receptors on the proliferation of vascular smooth muscle cells.

含Gla蛋白及其受体对血管平滑肌细胞增殖的影响分析。

基本信息

批准号：
08671240
负责人：
TSUDA Hiroko
金额：
$ 1.47万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671240/
关键词：
Protein S Gas6 Receptor tyrosine kinase Vascular smooth muscle cells Protein S Gas 6 血管平滑筋細胞

项目摘要

Novel receptor tyrosine kinases including Sky, which we have cloned from a Hep G2 cDNA library, Axl/Ufo and Mer/Eyk form a subfamily based on a unique extracellular domain. Recently gamma-carboxyglutamic acid (Gla)-containing proteins, protein S and Gas6, have been reported to be physiological ligands for the Axl/Sky subfamily of receptor tyrosine kinases. In this study, we tried to elucidate the physiological importance of the novel signaling pathway mediated by this ligand-receptor system in the proliferation of vascular smooth muscle cells.Both human protein S and rat Gas6 failed to induce proliferation of rat arterial vascular smooth muscle cells, however, rat Gas6 potentiated the mitogenic activity of thrombin as reported by Nakano et al. Species specificity has been reported to exist in the interaction between protein S or Gas6 and Axl/Sky receptor subfamily, we are now analyzing the effect of human protein S on the proliferation of bovine and human vascular smooth muscle cells.Analysis of the binding ability of the soluble receptors of human Axl, human Sky and mouse Mer composed of the extracellular domain of receptors fused to the Fc domain of immunoglobulin G1 showed that rat Gas6, but not human protein S,bound to Axl, Sky and Mer. The C-terminal sex hormone-binding globulin-like domain of Gas6 was indispensable for the binding of Gas6 to Axl and the N-terminal Gla domain had a regulatory role on the interaction.We developed a swine model of coronary spasms with intimal thickening by chronically treating the outside of the coronary arteries with a inflammatory cytokine, IL-1beta. In order to know whether the novel signaling pathway mediated by binding protein S and Gas6 to Axl/Sky receptor family is implicated in formation of the vasospastic lesions, we proceed to determine the expression of these molecules in the lesions with proliferation of vascular smooth muscle cells.

新型受体酪氨酸激酶包括我们从 Hep G2 cDNA 文库中克隆的 Sky、Axl/Ufo 和 Mer/Eyk，形成基于独特胞外结构域的亚家族。最近，据报道，含有γ-羧基谷氨酸（Gla）的蛋白质、蛋白质S和Gas6是受体酪氨酸激酶Axl/Sky亚家族的生理配体。在本研究中，我们试图阐明这种配体-受体系统介导的新型信号通路在血管平滑肌细胞增殖中的生理重要性。人蛋白S和大鼠Gas6均未能诱导大鼠动脉血管平滑肌细胞增殖然而，据 Nakano 等人报道，大鼠 Gas6 增强了凝血酶的促有丝分裂活性。已有报道 Protein S 或 Gas6 与 Axl/Sky 受体亚家族的相互作用存在物种特异性，我们现在正在分析人 Protein S 对牛和人血管平滑肌细胞增殖的影响。由与免疫球蛋白 G1 的 Fc 结构域融合的受体胞外结构域组成的人 Axl、人 Sky 和小鼠 Mer 的可溶性受体显示，大鼠 Gas6（而非人蛋白 S）与Axl、Sky 和 Mer。 Gas6 的 C 端性激素结合球蛋白样结构域对于 Gas6 与 Axl 的结合是必不可少的，N 端 Gla 结构域对相互作用具有调节作用。使用炎症细胞因子 IL-1β 长期治疗冠状动脉外部。为了了解由蛋白S和Gas6与Axl/Sky受体家族结合介导的新信号通路是否与血管痉挛性病变的形成有关，我们继续测定这些分子在血管平滑肌细胞增殖的病变中的表达。