LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis

• Published in: Pharmacology & therapeutics (Oxford) 2002-07, Vol.95 (1), p.89-100
• Main Authors: Chen, Mingyi, Masaki, Tomoh, Sawamura, Tatsuya
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Arteriosclerosis - metabolism; Atherosclerosis; Cells, Cultured; Endothelial cell dysfunction; Endothelium, Vascular - metabolism; Humans; Lipoproteins, LDL - metabolism; LOX-1; Molecular Sequence Data; Myocytes, Smooth Muscle - metabolism; Oxidized low-density lipoproteins; Receptors, LDL - chemistry; Receptors, LDL - genetics; Receptors, LDL - metabolism; Receptors, Oxidized LDL; Scavenger receptor; Scavenger Receptors, Class E; Sequence Alignment
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/S0163-7258(02)00236-X

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was initially identified as the major receptor for oxidized LDL (OxLDL) in endothelial cells. Its inducible expression in macrophages and smooth muscle cell was also observed. LOX-1 is a Type II membrane protein with a typical C-type lectin structure at the extracellular C-terminus. It can be cleaved by an unknown protease at the extracellular juxtamembrane region to release the soluble form of LOX-1. The extracellular domains of LOX-1 are post-translationally modified by N-linked glycosylation. Mutagenesis studies revealed that the lectin domain of LOX-1 is the functional domain that recognizes the LOX-1 ligand. The C-terminal end residues and several conserved positively charged residues spanning the lectin domain are essential for OxLDL binding. LOX-1 activation by OxLDL causes endothelial changes that are characterized by activation of nuclear factor-κB through an increased reactive oxygen species, subsequent induction of adhesion molecules, and endothelial apoptosis. In vitro, expression of LOX-1 is induced by many inflammatory cytokines, oxidative stress, hemodynamic stimuli, and OxLDL. In vivo, the expression is enhanced in pro-atherogenic settings including, hypertension, hyperlipidemia, and diabetes, and, indeed, is accumulated in the atherosclerotic and glomerulosclerotic lesions. LOX-1 binds multiple classes of ligands that are implicated in the pathogenesis of atherosclerosis. Besides OxLDL, LOX-1 can recognize apoptotic/aged cells, activated platelets, and bacteria, implying versatile physiological functions. Taken together, all these findings support the possible contribution of LOX-1 to the pathogenesis of vascular disorders, particularly atherosclerosis. Development of antagonists for LOX-1 might be a good therapeutic approach to vascular diseases.