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(Circulation. 2005;112:1636-1643.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E–Null Mice

Masaru Iwai, MD, PhD; Rui Chen, MD, PhD; Zhen Li, MD, PhD; Tetsuya Shiuchi, PhD; Jun Suzuki, MD, PhD; Ayumi Ide, BS; Masahiro Tsuda, MD, PhD; Midori Okumura, MD; Li-Juan Min, MD; Masaki Mogi, MD, PhD; Masatsugu Horiuchi, MD, PhD

From the Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Received November 29, 2004; revision received April 21, 2005; accepted June 13, 2005.

Background— The role of angiotensin II (Ang II) type 2 (AT₂) receptor in atherosclerosis was explored with the use of AT₂ receptor/apolipoprotein E (ApoE)–double-knockout (AT₂/ApoE-DKO) mice, with a focus on oxidative stress.

Methods and Results— After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT₂/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47^phox was observed. These changes were also greater in AT₂/ApoE-DKO mice. An Ang II type 1 (AT₁) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47^phox expression; these inhibitory effects were significantly weaker in AT₂/ApoE-KO mice. We further examined the signaling mechanism of the AT₂ receptor–mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47^phox induced by Ang II were inhibited by valsartan but enhanced by an AT₂ receptor blocker, PD123319.

Conclusions— These results suggest that AT₂ receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT₂ receptor stimulation by unbound Ang II.

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