Published online before print July 15, 2002, doi: 10.1161/01.CIR.0000024103.04821.86
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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
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 AT1a in vascular remodeling.
Methods and Results— Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), 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 AT1aKO 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 AT1aKO 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-xL mRNA was enhanced in AT2KO mice but attenuated in AT1aKO 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 AT1a in the process of neointimal formation after vascular injury.
Key Words: angiotensin • receptors • apoptosis • arteries • remodeling
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