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Molecular mechanism of the process from atherosclerotic lesion formation to plaque rupture

动脉粥样硬化病变形成到斑块破裂过程的分子机制

基本信息

批准号：
16209031
负责人：
KITA Toru
金额：
$ 32.28万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209031/
关键词：
atherosclerosis Oxidized LDL receptor platelet LOX-1 granule secretion integrin prostaglandin chemokine

项目摘要

In this study we tried to elucidate the molecular mechanism involved in the process from atherosclerotic lesion formation to plaque rupture, a phenomenon involved in acute coronary syndrome. Kume in our group has found that the formation of a soluble form of LOX-1 (oxidized LDL receptor) was increased in the blood by thrombus formation in a transgenic mouse overexpressing human LOX-1 specifically in endothelia cells and smooth muscle cells. He also found that this soluble form of LOX-1 was increased in patients of acute coronary syndrome, indicating that this molecule could be a marker for acute coronary syndrome as well as for the development of atherosclerotic lesions. Arai, Kume, and Yokode in our group found that the novel oxidized LDL receptor, SR-PSOX (scavenger receptor for phosphatidylserine and oxidized low-density lipoprotein), which we cloned is the same molecule as α-chemokine, CXCL16. Our data showed that CXCL16 could induce angiogenesis by increasing endothelial proliferation, chemotaxis, and tube formation. The MAP kinase (ERK) was found to be involved in CXCL16-induced angiogenesis. Horiuchi in our group established a semi-intact assay to analyze the molecular mechanism of aggregation and granule secretion of platelets using permeabilized platelets. Using this system he found that Rab27 regulated the dense core granule secretion in platelets by employing its binding protein, Munc13-4. Nakamura in our group found that fibulin-5 mRNA was increased in the mouse atherosclerotic lesions and pulmonary hypertension model.

在这项研究中，我们试图阐明从动脉粥样硬化病变的形成过程中的分子机制，斑块破裂，一个现象涉及急性冠状动脉综合征。本课题组的久米发现，在内皮细胞和平滑肌细胞中特异性过表达人LOX-1的转基因小鼠中，通过血栓形成，血液中可溶性LOX-1（氧化LDL受体）的形成增加。他还发现，这种可溶性LOX-1在急性冠状动脉综合征患者中增加，表明这种分子可能是急性冠状动脉综合征以及动脉粥样硬化病变发展的标志物。本研究组的Arai、Kume和Yokode发现，我们克隆的新型氧化LDL受体SR-PSOX（磷脂酰丝氨酸和氧化低密度脂蛋白的清道夫受体）与α-趋化因子CXCL 16是相同的分子。我们的数据表明，CXCL 16可以通过增加内皮细胞增殖、趋化性和管形成来诱导血管生成。发现MAP激酶（ERK）参与CXCL 16诱导的血管生成。Horiuchi等人建立了一种半完整的方法，利用透化血小板分析血小板聚集和颗粒分泌的分子机制。使用这个系统，他发现Rab 27通过使用其结合蛋白Munc 13 -4来调节血小板中致密核心颗粒的分泌。本课题组中村等发现在小鼠动脉粥样硬化病变和肺动脉高压模型中fibulin-5 mRNA表达增加。