Investigations for developing novel diagnostic methods, therapeutics, and drugs utilizing lectin-like oxidized LDL receptor-1 (LOX-1)

利用凝集素样氧化 LDL 受体 1 (LOX-1) 开发新型诊断方法、治疗方法和药物的研究

• 批准号: 11557006
• 负责人: SAWAMURA Tatsuya
• 金额: $ 8.7万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557006/
• 关键词: oxidized LDL; oxidized LDL receptor; LOX-1; transgenic mouse; endothelial cells; ノックアウトマウス; 動脈硬化; 炎症; レクチン様酸化LDL受容体; LOX-1リガンド; 内皮細胞; 血小板

We cloned human LOX-1 gene, and determined its structure and localization at short arm of 12th chromosome. Analyses of expression profile of LOX-1 showed that LOX-1 expression is induced by oxidized LDL, inflammatory cytokines, hypertension, diabetes, and hyperlipidemia.From the functional aspect, we found that LOX-1 induces generation of superoxide anion and reduction in nitric oxide in endothelial cells, binding oxidized LDL. Activated platelets and leukocytes were found as novel ligands for LOX-1.To clarify pathological significance of LOX-1, we generated ApoE(-/-)/LOX-1tg mice, which overexpress LOX-1 in the vasculature and muscle in heart, and found that overexpression of LOX-1 accelerates atherosclerosis in coronary artery. In this model accumulation of oxidized LDL and macrophages was also enhanced. We also revealed the involvement of LOX-1 in inflammation, employing models of endotoxin-induced uveites and zymosan-induced arthritis, showing the effectiveness of the treatment with ant-LOX-1 antibody. Furthermore, treatment with anti-LOX-1 antibody siginificantly reduced infarct size in rat model of myocardial infarction. Taken together, LOX-1 is involved in, and anti-LOX-1 therapy would be effective for various disease.

我们克隆了人LOX-1基因，并测定了其结构和定位于第12号染色体短臂。LOX-1的表达谱分析表明LOX-1的表达受氧化型LDL、炎症因子、高血压、糖尿病和高脂血症的诱导，从功能方面我们发现LOX-1通过与氧化型LDL结合，诱导内皮细胞产生超氧阴离子和减少一氧化氮。为了阐明LOX-1的病理学意义，我们建立了在心脏血管和肌肉中过表达LOX-1的ApoE（-/-）/LOX-1 tg小鼠，发现LOX-1的过表达促进冠状动脉粥样硬化。在该模型中，氧化LDL和巨噬细胞的积累也增强。我们还揭示了LOX-1参与炎症，采用内毒素诱导的葡萄膜炎和酵母多糖诱导的关节炎模型，显示了抗LOX-1抗体治疗的有效性。此外，用抗LOX-1抗体治疗显著减少了心肌梗死大鼠模型中的梗死面积。总之，LOX-1参与了多种疾病，抗LOX-1治疗对各种疾病都有效。

项目成果

Li, D.: "LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells"Circulation. 107. 612-617 (2003)

Li, D.：“LOX-1 介导氧化低密度脂蛋白诱导的人冠状动脉内皮细胞中基质金属蛋白酶的表达”循环。

Nakagawa, T.: "LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-included cell death---possible role of dephosphorylation of Akt"Biochem Biophys Res Commun. 299. 91-97 (2002)

Nakakawa, T.：“培养的大鼠软骨细胞中表达的 LOX-1 介导氧化 LDL 细胞死亡——Akt 去磷酸化的可能作用”Biochem Biophys Res Commun。

Aoyama, T.: "Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells"J Mol Cell Cardiol. 31. 2101-2114 (1999)

Aoyama, T.：“在培养的内皮细胞中通过氧化 LDL 和溶血磷脂酰胆碱诱导凝集素样氧化 LDL 受体”J Mol Cell Cardiol。

Iwakura, A: "Pericardial Fluid from Patients with Ichemic Heart Disease Induces Myocardial Cell Apoptotis via an Oxidant Stress-sensitive p38 Mitogen-activated Protein Kinase Pathway"J Mol Cell Cardiol. 33. 419-430 (2001)

Iwakura, A：“缺血性心脏病患者的心包液通过氧化应激敏感的 p38 丝裂原激活蛋白激酶途径诱导心肌细胞凋亡”J Mol Cell Cardiol。

Chen, M: "Diabetes enhances lectin-like oxidized LDL receptor-I (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and age"Biochem Biophys Res Commun. 287. 962-968 (2001)

Chen, M：“糖尿病增强血管内皮细胞中凝集素样氧化 LDL 受体-I (LOX-1) 的表达：LOX-1 配体和年龄的可能作用”Biochem Biophys Res Commun。