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

Mingyi Chen, Tomoh Masaki, Tatsuya Sawamura

Research output: Contribution to journalReview articlepeer-review

289 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalPharmacology and Therapeutics
Volume95
Issue number1
DOIs
StatePublished - 2002

Keywords

  • Atherosclerosis
  • Endothelial cell dysfunction
  • LOX-1
  • Oxidized low-density lipoproteins
  • Scavenger receptor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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