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.

我们已经研究了参与动脉粥样硬化形成早期的内皮细胞激活的分子机制，并在结果之后获得了。（1）在世界各地的实验室中，在包括我们在内的世界各地的实验室中都证明了低密度脂蛋白（LDL）的氧化。我们发现其可溶性的LOX-1形式存在，我们在内皮细胞上已将其确定为氧化的LDL受体。我们还发现了LOX-1糖基化的机制，并证明了糖化在LOX功能中的重要性。（2）在LDL氧化过程中产生的溶物磷脂酰胆碱（LPC），这是在LDL氧化过程中产生的，增强了几种基因表达的表达，涉及通过EGF-1表达的动脉粥样硬化形成的几个基因。动脉瘤斑块中的分子，证明了棒形细菌与内皮细胞结合的重要性。（4）对于动脉粥样硬化的形成，巨噬细胞的迁移已显示出至关重要的作用。我们发现，趋化因子MCP-1采用细胞内信号传导的不同途径进行细胞跟踪和迁移。（5）动脉粥样硬化的最后一步是血栓形成，是由血小板激活触发的。我们发现，我们最近确定的果酱，连接粘附分子也在血小板中表达，并在血小板激活后磷酸化。此外，我们已经建立了一个半完整的血小板聚集和颗粒分泌系统。我们证明了小型GTPase Rho在Aggregation和Rab4中的参与。