The role of reactive oxygen species in TNFα-dependent expression of the receptor for advanced glycation end products in human umbilical vein endothelial cells

Engagement of the receptor for advanced glycation end products (RAGE) by its signal transduction ligands is implicated in the development and progression of atherosclerosis. TNFα, a proinflammatory cytokine, is a potent inducer of RAGE expression in endothelial cells. In the present study, we demonstrate that reactive oxygen species (ROS) generated by TNFα stimulated human umbilical vein endothelial cells (HUVECs) induce RAGE expression. The complex III of mitochondrial respiratory chain appears to be the primary source of ROS. The gp91phox subunit of NADPH oxidase appears to be the source of ROS that induces TNFα-dependent mitochondrial ROS generation and subsequent RAGE expression. We also demonstrate that the ROS-mediated RAGE induction occurs via activation of NF-κB, a proinflammatory transcription factor. Thus, stimulation of HUVECs by TNFα evokes the following sequence of events: stimulation of NADPH oxidase → generation of ROS → activation of the mitochondrial respiratory chain → stimulation of NF-κB activity → induction of RAGE expression.