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(Circulation. 2002;106:847.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Role of Angiotensin II–Regulated Apoptosis Through Distinct AT₁ and AT₂ Receptors in Neointimal Formation

Jun Suzuki, MD; Masaru Iwai, MD, PhD; Hironori Nakagami, MD; Lan Wu, MD; Rui Chen, MD; Takashi Sugaya, PhD; Mareomi Hamada, MD, PhD; Kunio Hiwada, MD, PhD; Masatsugu Horiuchi, MD, PhD

From the Department of Medical Biochemistry (J.S., M.I., H.N., L.W., R.C., M.H.) and the Second Department of Internal Medicine (J.S., M.H., K.H.), Ehime University School of Medicine, Ehime, Japan; and Discovery Research Laboratory (T.S.), Tanabe Seiyaku Co, Osaka, Japan.

Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

Background— In vitro studies suggest that angiotensin II type 1 and type 2 (AT₁ and AT₂) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT₂ exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT_1a in vascular remodeling.

Methods and Results— Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT_1a-null (AT_1aKO), AT₂-null (AT₂KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT₂KO mice, but they were both suppressed in AT_1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT_1aKO mice but decreased in AT₂KO mice. Reverse transcriptase–polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT₂KO mice. On the other hand, the expression of bcl-2 and bcl-x_L mRNA was enhanced in AT₂KO mice but attenuated in AT_1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results.

Conclusions— Our results suggest that AT₂ exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT_1a in the process of neointimal formation after vascular injury.

Key Words: angiotensin • receptors • apoptosis • arteries • remodeling

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