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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:e138.)
© 2006 American Heart Association, Inc.

Vascular Biology

Blockade of Angiotensin II Receptors Reduces the Expression of Receptors for Advanced Glycation End Products in Human Endothelial Cells

Masashi Fujita; Hiroko Okuda; Osamu Tsukamoto; Yoshihiro Asano; Yulin Liao Akio Hirata; Jiyoong Kim; Takeshi Miyatsuka; Seiji Takashima; Tetsuo Minamino; Hitonobu Tomoike; Masafumi Kitakaze

From the Department of Cardiovascular Medicine (M.F., H.O., O.T., Y.A., Y.L., A.H., T. Miyatsuka, S.T., T. Minamino), Osaka University Graduate School of Medicine, Suita; and Cardiovascular Division of Medicine (H.O., O.T., J.K., H.T., M.K.), National Cardiovascular Center of Japan, Suita, Japan.

Correspondence to Masafumi Kitakaze, MD, PhD, Cardiovascular Division of Medicine, National Cardiovascular Center of Japan, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

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.

We investigated whether an angiotensin II type-1 receptor blocker (ARB) exerts antiatherosclerotic effects via inhibiting TNF-RAGE interaction. ARBs decreased TNF-induced RAGE expression in human endothelial cells along with the decrease in the activity of NF-B and the expression of inflammatory mediators. ARBs exert antiatherosclerotic effects via reducing TNF-RAGE interaction.

Key Words: angiotensin II type-1 receptor blocker (ARB) • receptors for advanced glycation end products (RAGEs) • endothelial cell