Objectives--Receptors for advanced glycation end products (RAGEs) play crucial roles in atherogenesis. Because tumor necrosis factor (TNF) is expressed and upregulates RAGE expression in atherosclerotic lesions, the TNF-RAGE interaction might be involved in the inflammatory process of atherogenesis. On the other hand, an angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to have also antiatherosclerotic effects. Thus we investigated whether an ARB exerts antiatherosclerotic effects via inhibiting the TNF-RAGE interaction.

Methods and Results--Stimulation of human endothelial cells with candesartan as well as olmesartan decreased TNF-induced RAGE expression in both mRNA and protein levels along with the decrease in the activity of nuclear factor B and the expression of inflammatory mediators such as vascular cell adhesion molecule (VCAM)-1. Both candesartan and olmesartan inhibited the binding of nuclear factor B to the RAGE gene promoter. Furthermore, gene silencing of RAGE by RNA interference decreased the expression of TNF-induced VCAM-1 in both mRNA and protein levels.

Conclusions--RAGE contributes at least partially to the TNF-induced VCAM-1 expression in both mRNA and protein levels. Blockade of angiotensin II receptors might exert antiatherosclerotic effects via reducing TNF-RAGE interaction.