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

我们对动脉粥样硬化形成早期中内皮细胞激活的分子机制进行了研究，取得了以下结果：(1)包括我们在内的世界各地的实验室都证实了低密度脂蛋白(LDL)氧化在动脉粥样硬化形成中的作用。我们已经发现了其可溶性形式LOX-1的存在，我们已经确定它是内皮细胞上的氧化型低密度脂蛋白受体。我们还发现了LOX-1的糖基化机制，证明了糖基化在LOX功能中的重要性。(2)在低密度脂蛋白氧化过程中产生的溶血磷脂酰胆碱(LPC)通过EGF-1的表达促进了几个参与动脉粥样硬化形成的基因的表达。(3)我们发现了一种新的氧化低密度脂蛋白受体SR-PSOX。我们在动脉粥样硬化的斑块中发现了该分子的表达，证明了杆状细菌与内皮细胞结合的重要性。(4)在动脉粥样硬化的形成中，巨噬细胞的迁移被证明发挥了关键作用。我们发现一种趋化因子MCP-1通过不同的细胞内信号通路来实现细胞的附着和迁移。(5)动脉粥样硬化的最后一步是血栓形成，它是由血小板激活引发的。我们发现，我们最近发现的JAM，即我们最近发现的连接黏附分子，也在血小板中表达，并在血小板激活时被磷酸化。此外，我们还建立了一个半完整的血小板聚集和颗粒分泌系统。我们证明了小分子GTP酶Rho参与聚集，Rab4参与α-颗粒分泌，这些结果在国际动脉粥样硬化会议、欧洲生命科学会议、美国心脏协会会议等国际科学会议上发表。

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.