Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway

Antioxid Redox Signal. 2008 Oct;10(10):1699-712. doi: 10.1089/ars.2007.1999.


The accumulation of advanced oxidation protein products (AOPPs) has been linked to vascular lesions in diabetes, chronic renal insufficiency, and atherosclerosis. However, the signaling pathway involved in AOPPs-induced endothelial cells (ECs) perturbation is unknown and was investigated. AOPPs modified human serum albumin (AOPPs-HSA) bound to the receptor for advanced glycation end products (RAGE) in a dose-dependent and saturable manner. AOPPs-HSA competitively inhibited the binding of soluble RAGE (sRAGE) with its preferential ligands advanced glycation end products (AGEs). Incubation of AOPPs, either prepared in vitro or isolated from uremic serum, with human umbilical vein ECs induced superoxide generation, activation of NAD(P)H oxidase, ERK 1/2 and p38, and nuclear translocation of NF-kappaB. Activation of signaling pathway by AOPPs-ECs interaction resulted in overexpression of VCAM-1 and ICAM-1 at both gene and protein levels. This AOPPs-triggered biochemical cascade in ECs was prevented by blocking RAGE with either anti-RAGE IgG or excess sRAGE, but was not affected by the neutralizing anti-AGEs IgG. These data suggested that AOPPs might be new ligands of endothelial RAGE. AOPPs-HSA activates vascular ECs via RAGE-mediated signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Cells, Cultured / metabolism
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Immunoglobulin G / pharmacology
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • MAP Kinase Signaling System
  • Membrane Glycoproteins / physiology
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases / physiology
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Reactive Oxygen Species / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / physiology*
  • Serum Albumin / pharmacology*
  • Signal Transduction / physiology
  • Umbilical Veins / cytology
  • Uremia / blood
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Glycation End Products, Advanced
  • Immunoglobulin G
  • Membrane Glycoproteins
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Serum Albumin
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • CYBA protein, human
  • neutrophil cytosolic factor 1