LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis.
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-kappaB 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.
Chen
Mingyi
M
National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Masaki
Tomoh
T
Sawamura
Tatsuya
T
D000595:Amino Acid Sequence; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D016415:Sequence Alignment
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein