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.