Circulation. 2002;105:816-822
Published online before print January 22, 2002, doi: 10.1161/hc0702.104183
Published online before print January 22, 2002, doi: 10.1161/hc0702.104183
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(Circulation. 2002;105:816.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Advanced Glycation End Products Activate Endothelium Through Signal-Transduction Receptor RAGE
A Mechanism for Amplification of Inflammatory Responses
From CNR Institute of Clinical Physiology, Pisa, Italy (G.B., G.L., M.M., T.S., R.D.C.); Institute of Pathology, University of Siena, Siena, Italy (P.T.); G. d’Annunzio University, Chieti, Italy (R.D.C.); and College of Physicians and Surgeons, Columbia University, New York, NY (C.F., T.K., D.M.S., A.M.S.).
Correspondence to Raffaele De Caterina, MD, PhD, University Cardiology Division, G. d’Annunzio University of Chieti, Ospedale S Camillo de Lellis, Via Forlanini, 50, I–66100 Chieti, Italy. E-mail rdecater{at}unich.it
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.
Methods and 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 N
(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.
Key Words: cell adhesion molecules • receptors • endothelium • inflammation • vasculature
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