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

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。总而言之，LOX-1参与其中，抗LOX-1治疗对各种疾病都有效。

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.