Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses.
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.
Basta
Giuseppina
G
CNR Institute of Clinical Physiology, Pisa, Italy.
Lazzerini
Guido
G
Massaro
Marika
M
Simoncini
Tommaso
T
Tanganelli
Piero
P
Fu
Caifeng
C
Kislinger
Thomas
T
Stern
David M
DM
Schmidt
Ann Marie
AM
De Caterina
Raffaele
R
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
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