Pathophysiological roles of LOX-1, a novel receptor of oxidized LDL

LOX-1（一种氧化 LDL 的新型受体）的病理生理学作用

• 批准号: 11838008
• 负责人: KUME Noriaki
• 金额: $ 2.62万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11838008/
• 关键词: atherosclerosis; hyperlipidemia; oxidized LDL; scavenger receptor; apoptosis; smooth muscle cells; plaque rupture; LOX-1; スカベンジカー受容体; Bax; Bcl-2

Lectin-like Ox-LDL receptor-1 (LOX-1) is a type-II membrane glycoprotein belonging to the C-type lectin family, and acts as a cell surface endocytosis receptor for atherogenic oxidized LDL (Ox-LDL). LOX-1 can support binding, internalization, and proteolytic degradation of Ox-LDL, but not of significant amounts of acetylated LDL, which is a well-know high-affinity ligand for class A scavenger receptors. LOX-1 is initially synthesized as a 40 kDa precursor protein with N-linked high mannose-type carbohydrate, which is further glycosylated and processed into a 50 kDa mature form. LOX-1 expression is not constitutive but can dynamically be induced by proinflammatory stimuli, such as TNF-α and TGF-β, and a mechanical stimulus, fluid shear stress. LOX-1 expression is also detectable in cultured macrophages and activated vascular smooth muscle cells. In vivo, endothelial cells covering early atherosclerotic lesions and intimal macrophages and smooth muscle cells in advanced atherosclerotic plaques expressed LOX-1 at high levels. Cell-surface LOX-1 can be cleaved by certain protease activities associated with the plasma membrane and released into the culture media. Purification of soluble LOX-1 and the N-terminal amino acid sequencing identified the two cleavage sites, Arg^<86>-Ser^<87> and Lys^<89>-Ser^<90>, both of which were located in the membrane proximal extracellular domain of LOX-1. Ox-LDL induced apoptosis of cultured bovine aortic smooth muscle cells (BSMC). Ox-LDL also induced Bax and down-regulated Bcl-2 expression, Which was partially inhibited by anti-LOX-1 monoclonal antibody, suggesting that LOX-1-mediated endocytosis or binding of Ox-LDL is, at least in part, involved in Ox-LDL-induced apoptosis of BSMC.Because Ox-LDL-induced SMC apoptosis may be a key event in atherosclerotic plaque rupture and the onset of acute coronary syndromes, measurement of soluble LOX-1 in vivo may provide a novel diagnostic molecular marker to predict the disease status.

凝集素样氧化低密度脂蛋白受体-1（LOX-1）是C型凝集素家族的一种II型膜糖蛋白，是氧化低密度脂蛋白（Ox-LDL）的细胞表面内吞受体。LOX-1可以支持Ox-LDL的结合、内化和蛋白水解降解，但不能支持大量乙酰化LDL的结合、内化和蛋白水解降解，乙酰化LDL是A类清道夫受体的众所周知的高亲和力配体。LOX-1最初合成为具有N-连接的高甘露糖型碳水化合物的40 kDa前体蛋白，其进一步糖基化并加工成50 kDa成熟形式。LOX-1的表达不是组成性的，而是可以被促炎刺激物（如TNF-α和TGF-β）和机械刺激物（流体剪切应力）动态诱导。LOX-1的表达也可在培养的巨噬细胞和活化的血管平滑肌细胞中检测到。在体内，覆盖早期动脉粥样硬化病变的内皮细胞以及晚期动脉粥样硬化斑块中的内膜巨噬细胞和平滑肌细胞高水平表达LOX-1。细胞表面LOX-1可被与质膜相关的某些蛋白酶活性切割并释放到培养基中。可溶性LOX-1的纯化和N-末端氨基酸序列分析确定了两个切割位点，Arg^<86>-Ser^<87>和Lys^<89>-Ser^<90>，这两个位点都位于LOX-1的近膜胞外结构域。Ox-LDL诱导培养的牛主动脉平滑肌细胞凋亡。Ox-LDL诱导的BSMC凋亡可能是动脉粥样硬化斑块破裂和急性冠状动脉综合征发病的关键事件，体内可溶性LOX-1的测定可提供一种新的诊断性分子标记物来预测疾病状态。

项目成果

Takashi Shimaoka Noriaki Kume et al: "LOX-1 supports Gram.positive and Gram.negative bacteria"The Journal of Immunology. (印刷中). (2001)

Takashi Shimaoka Noriaki Kume 等人：“LOX-1 支持革兰氏阳性和革兰氏阴性细菌”《免疫学杂志》（2001 年）。

Manabu Minami Noriaki Kume et al: "Transforming growth factor β1 increases the expression of lectin-like oxidized low density lipoprotein receptor-1"Biochem.Biophys.Res.Commun.. vol.272. 357-361 (2000)

Manabu Minami Noriaki Kume 等人：“转化生长因子 β1 增加凝集素样氧化低密度脂蛋白受体-1 的表达”Biochem.Biophys.Res.Commun. vol.272 (2000)。

Kataoka H,Kume N et al.: "Biosynthesis and post translational processing of lectin-like oxidized low density lipoprotein receptor 1 (LOX-1)."The Journal of Biological Chemistry. 275. 6573-6579 (2000)

Kataoka H、Kume N 等人：“凝集素样氧化低密度脂蛋白受体 1 (LOX-1) 的生物合成和翻译后加工。”生物化学杂志。

Takeshi Shimaoka Noriaki Kume et al: "Molecular cloning of a novel scavenger receptor for phosphatidyserine and oxidized low density lipoprotein SP-PSOX, on maco phay"The Journal of Biological Chemisty. vol.275. 40663-40666 (2000)

Takeshi Shimaoka Noriaki Kume 等人：“在 maco phay 上对磷脂酰丝氨酸和氧化低密度脂蛋白 SP-PSOX 的新型清道夫受体进行分子克隆”《生物化学杂志》。

Kataoka,H.: "Expression of lectin-like oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions"Circulation. 99(24). 3110-3117 (1999)

Kataoka,H.：“人类动脉粥样硬化病变中凝集素样氧化低密度脂蛋白受体 1 的表达”循环。