Pathophysiological roles of LOX-1, a novel receptor of oxidized LDL

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Lectin-like Ox-LDL receptor-1 (LOX-1) is a type-II membrane glycoprotein belonging to the C-type lectin family, and acts as a cell surface endocytosis receptor for atherogenic oxidized LDL (Ox-LDL). LOX-1 can support binding, internalization, and proteolytic degradation of Ox-LDL, but not of significant amounts of acetylated LDL, which is a well-know high-affinity ligand for class A scavenger receptors. LOX-1 is initially synthesized as a 40 kDa precursor protein with N-linked high mannose-type carbohydrate, which is further glycosylated and processed into a 50 kDa mature form. LOX-1 expression is not constitutive but can dynamically be induced by proinflammatory stimuli, such as TNF-α and TGF-β, and a mechanical stimulus, fluid shear stress. LOX-1 expression is also detectable in cultured macrophages and activated vascular smooth muscle cells. In vivo, endothelial cells covering early atherosclerotic lesions and intimal macrophages and smooth muscle cells in advanced atherosclerotic plaques expressed LOX-1 at high levels. Cell-surface LOX-1 can be cleaved by certain protease activities associated with the plasma membrane and released into the culture media. Purification of soluble LOX-1 and the N-terminal amino acid sequencing identified the two cleavage sites, Arg^<86>-Ser^<87> and Lys^<89>-Ser^<90>, both of which were located in the membrane proximal extracellular domain of LOX-1. Ox-LDL induced apoptosis of cultured bovine aortic smooth muscle cells (BSMC). Ox-LDL also induced Bax and down-regulated Bcl-2 expression, Which was partially inhibited by anti-LOX-1 monoclonal antibody, suggesting that LOX-1-mediated endocytosis or binding of Ox-LDL is, at least in part, involved in Ox-LDL-induced apoptosis of BSMC.Because Ox-LDL-induced SMC apoptosis may be a key event in atherosclerotic plaque rupture and the onset of acute coronary syndromes, measurement of soluble LOX-1 in vivo may provide a novel diagnostic molecular marker to predict the disease status.