title: Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses.
abstract: BACKGROUND
  The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation.
  
  
  RESULTS
  AGEs, RAGE, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin are expressed in an overlapping manner in human inflamed rheumatoid synovia, especially within the endothelium. In primary cultures of human saphenous vein endothelial cells, engagement of RAGE by heterogeneous AGEs or Nepsilon(carboxymethyl)lysine-modified adducts enhanced levels of mRNA and antigen for vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. AGEs increased adhesion of polymorphonuclear leukocytes to stimulated endothelial cells in a manner reduced on blockade of RAGE.
  
  
  CONCLUSIONS
  AGEs, through RAGE, may prime proinflammatory mechanisms in endothelial cells, thereby amplifying proinflammatory mechanisms in atherogenesis and chronic inflammatory disorders.
authors.affiliation: CNR Institute 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: Marika
authors.initials: M
authors.lastname: Massaro
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Piero
authors.initials: P
authors.lastname: Tanganelli
authors.forename: Caifeng
authors.initials: C
authors.lastname: Fu
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012501:Saphenous Vein / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019040:E-Selectin; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1