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(Hypertension. 2005;45:1188.)
© 2005 American Heart Association, Inc.

Original Articles

Renin-Angiotensin System Modulates Oxidative Stress–Induced Endothelial Cell Apoptosis in Rats

Masahiro Akishita; Kumiko Nagai; Hang Xi; Wei Yu; Noriko Sudoh; Tokumitsu Watanabe; Mica Ohara-Imaizumi; Shinya Nagamatsu; Koichi Kozaki; Masatsugu Horiuchi; Kenji Toba

From the Department of Geriatric Medicine (M.A., K.N., H.X., W.Y., N.S., K.K., K.T.), Kyorin University School of Medicine, Tokyo, Japan; Department of Geriatric Medicine (T.W.), Graduate School of Medicine, University of Tokyo, Japan; Department of Biochemistry (M.O.-I., S.N.), Kyorin University School of Medicine, Tokyo, Japan; Department of Medical Biochemistry (M.H.), Ehime University School of Medicine, Japan.

Correspondence to Masahiro Akishita, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail akishita-tky{at}umin.ac.jp

The role of the renin-angiotensin system in oxidative stress–induced apoptosis of endothelial cells (ECs) was investigated using a rat model and cultured ECs. EC apoptosis was induced by 5-minute intra-arterial treatment of a rat carotid artery with 0.01 mmol/L H₂O₂ and was evaluated at 24 hours by chromatin staining of en face specimens with Hoechst 33342. Although activity of angiotensin-converting enzyme in arterial homogenates was not increased, administration of an angiotensin-converting enzyme inhibitor temocapril for 3 days before H₂O₂ treatment inhibited EC apoptosis, followed by reduced neointimal formation 2 weeks later. Also, an angiotensin II type 1 (AT1) receptor blocker (olmesartan) inhibited EC apoptosis, whereas angiotensin II administration accelerated apoptosis independently of blood pressure. Next, cultured ECs derived from a bovine carotid artery were treated with H₂O₂ to induce apoptosis, as evaluated by DNA fragmentation. Combination of angiotensin II and H₂O₂ dose-dependently increased EC apoptosis and 8-isoprostane formation, a marker of oxidative stress. Conversely, temocapril and olmesartan reduced apoptosis and 8-isoprostane formation induced by H₂O₂, suggesting that endogenous angiotensin II interacts with H₂O₂ to elevate oxidative stress levels and EC apoptosis. Neither an AT2 receptor blocker, PD123319, affected H₂O₂-induced apoptosis, nor a NO synthase inhibitor, N^G-nitro-L-arginine methyl ester, influenced the effect of temocapril on apoptosis in cell culture experiments. These results suggest that AT1 receptor signaling augments EC apoptosis in the process of oxidative stress–induced vascular injury.

Key Words: angiotensin • apoptosis • carotid arteries • endothelium • free radicals

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