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

在这项研究中，我们试图阐明从动脉粥样硬化病变形成到斑块破裂过程的分子机制，斑块破裂是一种涉及急性冠状动脉综合征的现象。我们小组的Kume发现，在内皮细胞和平滑肌细胞中过度表达人LOX-1的转基因小鼠中，血栓形成增加了血液中可溶性LOX-1（氧化LDL受体）的形成。他还发现，这种可溶性形式的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。本小组的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清除率受体）与α-趋化因子CXCL16是相同的分子。我们的数据显示，CXCL16可以通过增加内皮细胞增殖、趋化性和管的形成来诱导血管生成。MAP激酶（ERK）参与了cxcl16诱导的血管生成。我们组Horiuchi建立了一种半完整的方法，利用通透性血小板分析血小板聚集和颗粒分泌的分子机制。利用该系统，他发现Rab27通过其结合蛋白Munc13-4调节血小板中致密核心颗粒的分泌。我们组Nakamura发现，在小鼠动脉粥样硬化病变和肺动脉高压模型中，纤维蛋白-5 mRNA升高。

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.