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