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Molecular mechanism of activation of endothelial cells involved in early stage of atherosclerosis formation.

内皮细胞活化参与动脉粥样硬化形成早期的分子机制。

基本信息

批准号：
11307018
负责人：
KITA Toru
金额：
$ 23.55万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

We have studied Molecular mechanism of activation of endothelial cells involved in early stage of atherosclerosis formation and obtained following results.(1) Oxidization of low density lipoprotein (LDL) has been demonstrated in atherosclerossis formation by laboratories around the world including us. We have found existence of its soluble form of LOX-1, which we had identified as a oxidized LDL receptor on endothelial cells. We also found the mechanism of glycation of LOX-1 and demonstrated the importance of the glycation in the LOX function.(2) Lysophosphatidylcholine (LPC) which was produced during the process of LDL oxidization enhanced expression of several genes involved in atherosclerosis formation via Egf-1 expression.(3) We identified a novle oxidized LDL receptor named SR-PSOX.We found expression of the molecule in the atheromatous plaque and demonstrated the importance in binding of rod-shaped bacteria to endothelial cells.(4) For the formation of atherosclerosis, migration of macrophages has been shown to play a critical role. We found that a chemoattractant factor, MCP-1, employs distinct pathways of intracellular signaling for cell-attachment and migration.(5) The last step of the atherosclerosis is thrombosis formation which is triggered by platelet activation. We found that JAM, junctional adhesion molecule which we identified recently, was also expressed in platelets and phosphorylated upon platelet activation. Furthermore, we have established a semi-intact system for platelet aggregation and granule secretion. We demonstrated that thje involvement of small GTPase Rho in aggregation and Rab4 in a-granule secretion.These results were presented in many international scientific meeting such as the International Atherosclerosis Meeting, European Life Science Meeting, and American Heart Association Meeting.

我们对内皮细胞活化参与动脉粥样硬化早期形成的分子机制进行了研究，得到了以下结果：(1)低密度脂蛋白(LDL)的氧化作用已被包括我们在内的世界各地的实验室证实在动脉粥样硬化形成中。我们发现了其可溶形式的 LOX-1 的存在，我们将其鉴定为内皮细胞上的氧化 LDL 受体。我们还发现了LOX-1的糖化机制，并证明了糖化在LOX功能中的重要性。(2)LDL氧化过程中产生的溶血磷脂酰胆碱(LPC)通过Egf-1的表达增强了几个参与动脉粥样硬化形成的基因的表达。(3)我们鉴定了一种新型氧化LDL受体，命名为SR-PSOX。 (4)对于动脉粥样硬化的形成，巨噬细胞的迁移已被证明发挥着关键作用。我们发现趋化因子MCP-1利用不同的细胞内信号传导途径进行细胞附着和迁移。(5)动脉粥样硬化的最后一步是由血小板活化引发的血栓形成。我们发现 JAM（我们最近鉴定的连接粘附分子）也在血小板中表达，并在血小板激活时磷酸化。此外，我们还建立了血小板聚集和颗粒分泌的半完整系统。我们证明了小GTP酶Rho参与聚集，Rab4参与a颗粒分泌。这些结果在许多国际科学会议上发表，如国际动脉粥样硬化会议、欧洲生命科学会议和美国心脏协会会议。