Activation of NADPH oxidase by AGE links oxidant stress to altered gene
expression via RAGE.
Wautier, Marie-Paule, Olivier Chappey, Stefano Corda, David M. Stern, Ann Marie
Schmidt, and Jean-Luc Wautier.
1Laboratoire de Biologie Vasculaire et Cellulaire, Hôpital Lariboisiere, 2Unite
«inserm» 76, and 3Laboratoire Microcirculation, Biophysique Hopital Lariboisière, Paris,
France 75475; and 4College of Physicians and Surgeons, Columbia University, New
York, New York 10032
APStracts 8:0019E, 2001.
Engagement of the receptor for advanced glycation end products (RAGE) by products of
nonenzymatic glycation/oxidation triggers the generation of reactive oxygen species
(ROS), thereby altering gene expression. Because dissection of the precise events by
which ROS are generated via RAGE is relevant to the pathogenesis of complications in
AGE-related disorders, such as diabetes and renal failure, we tested the hypothesis that
activation of NADPH oxidase contributed, at least in part, to enhanced oxidant stress via
RAGE. Here we show that incubation of human endothelial cells with AGEs on the
surface of diabetic red blood cells, or specific AGEs, (carboxymethyl)lysine (CML)-
modified adducts, prompted intracellular generation of hydrogen peroxide, cell surface
expression of vascular cell adhesion molecule-1, and generation of tissue factor in a
manner suppressed by treatment with diphenyliodonium, but not by inhibitors of nitric
oxide. Consistent with an important role for NADPH oxidase, although macrophages
derived from wild-type mice expressed enhanced levels of tissue factor upon stimulation
with AGE, macrophages derived from mice deficient in a central subunit of NADPH
oxidase, gp91phox, failed to display enhanced tissue factor in the presence of AGE.
These findings underscore a central role of NADPH oxidase in AGE-RAGE-mediated
generation of ROS and provide a mechanism for altered gene expression in AGE-related
disorders.
Received 2 October 2000; accepted in final form 15 January 2001
APS Manuscript Number E453-0.
Article publication pending Am J Physiol Endocrinol Metab
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 27 February 2001