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

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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.