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，并对其结构和第12号染色体短臂上的定位进行了测定。LOX-1的表达谱分析表明，LOX-1的表达受氧化型低密度脂蛋白、炎性细胞因子、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诱导内皮细胞产生超氧阴离子，减少一氧化氮的产生，结合氧化型低密度脂蛋白。为了阐明LOX-1的病理意义，我们建立了ApoE(-/-)/LOX-1TG小鼠，在心脏的血管和肌肉中过表达LOX-1，发现LOX-1的过表达加速了冠状动脉的动脉粥样硬化。在这个模型中，氧化的低密度脂蛋白和巨噬细胞的积累也增加了。我们还利用内毒素诱导的葡萄膜和酵母多糖诱导的关节炎模型，揭示了LOX-1参与炎症反应，显示了ANT-LOX-1抗体治疗的有效性。此外，抗LOX-1抗体治疗显著减少了心肌梗死大鼠模型的心肌梗死范围。综上所述，LOX-1参与其中，抗LOX-1治疗可能对多种疾病有效。

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.