title: At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products.
abstract: OBJECTIVE
  The interaction of advanced glycation end products (AGEs) with their main receptor RAGE in endothelial cells induces intracellular generation of reactive oxygen species (ROS) and the expression of vascular cell adhesion molecule (VCAM)-1. We investigated the role of distinct sources of ROS, including the mitochondrial electron transport chain, NAD(P)H oxidase, xanthine oxidase, and arachidonic acid metabolism, in AGE-induced VCAM-1 expression.
  
  
  RESULTS
  The induction of ROS and VCAM-1 by AGEs in cultured human umbilical vein endothelial cells was specifically blocked by an anti-RAGE antibody. The inhibition of NAD(P)H oxidase by apocynin and diphenylene iodonium, and of the mitochondrial electron transport system at complex II by thenoyltrifluoroacetone (TTFA), significantly inhibited both AGE-induced ROS production and VCAM-1 expression, whereas these effects were potentiated by rotenone and antimycin A, specific inhibitors of mitochondrial complex I and III, respectively. The inhibition of Cu/Zn superoxide dismutase inhibited both ROS and VCAM-1 induction, indicating that H2O2 by this source is involved as a mediator of VCAM-1 expression by AGEs.
  
  
  CONCLUSIONS
  Altogether, these results demonstrate that ROS generated by both NAD(P)H-oxidase and the mitochondrial electron transport system are involved in AGE signaling through RAGE, and indicate potential targets for the inhibition of the atherogenic signals triggered by AGE-RAGE interaction.
authors.affiliation: C.N.R. Institutes of Clinical Physiology, Pisa, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Basta
authors.forename: Guido
authors.initials: G
authors.lastname: Lazzerini
authors.forename: Serena
authors.initials: S
authors.lastname: Del Turco
authors.forename: Gian Michele
authors.initials: GM
authors.lastname: Ratto
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D004579:Electron Transport / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D016718:Arachidonic Acid; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases