on April 21, 2005
Published online before print April 21, 2005, doi: 10.1161/01.ATV.0000167522.48370.5e
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Submitted on January 19, 2004
Accepted on April 8, 2005
At Least 2 Distinct Pathways Generating Reactive Oxygen Species Mediate Vascular Cell Adhesion Molecule-1 Induction by Advanced Glycation End Products
Giuseppina Basta ;
From the C.N.R. Institutes of Clinical Physiology (G.B., G.L., S.D.T., R.D.C.) and Neurophysiology (M.R.), Pisa, Italy; the College of Physicians and Surgeons (A.M.S.), Columbia University, New York, NY; and Chair of Cardiology (R.D.C.), "G. d’Annunzio" University, Chieti, Italy.
* To whom correspondence should be addressed. E-mail: rdecater{at}ifc.cnr.it.
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.
Methods and 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.
Key words: diabetes mellitus • endothelium • reactive oxygen species • signal transduction • superoxide • vascular biology • VCAM-1 • adhesion molecules
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