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

我们研究了参与动脉粥样硬化早期形成的内皮细胞活化的分子机制，得到以下结果。(1)低密度脂蛋白（LDL）的氧化作用在动脉粥样硬化形成过程中得到了包括我们在内的世界各地实验室的证实。我们已经发现其可溶性形式的LOX-1的存在，我们已经确定为内皮细胞上氧化的LDL受体。我们还发现了LOX-1糖基化的机制，并证明了糖基化在LOX功能中的重要性。(2)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的表达增强了几种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LDL受体，命名为SR-PSOX。我们在动脉粥样斑块中发现了该分子的表达，并证明了杆状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，巨噬细胞的迁移已被证明起着关键作用。我们发现一种化学引诱因子，MCP-1，在细胞附着和迁移中采用不同的细胞内信号传导途径。(5)动脉粥样硬化的最后一步是血小板活化引发的血栓形成。我们发现，我们最近发现的连接粘附分子JAM也在血小板中表达，并在血小板激活时磷酸化。此外，我们还建立了一个半完整的血小板聚集和颗粒分泌系统。我们证明了小GTPase Rho参与了a颗粒的聚集和Rab4参与了a颗粒的分泌。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。

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.