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(Hypertension. 2005;45:724.)
© 2005 American Heart Association, Inc.

Original Articles

Role of Rho-Kinase and p27 in Angiotensin II–Induced Vascular Injury

Takeshi Kanda; Koichi Hayashi; Shu Wakino; Koichiro Homma; Kyoko Yoshioka; Kazuhiro Hasegawa; Naoki Sugano; Satoru Tatematsu; Ichiro Takamatsu; Takayuki Mitsuhashi; Takao Saruta

From the Departments of Internal Medicine (T.K., K.H., S.W., K.H., K.Y., K.H., N.S., S.T., I.T., T.S.) and Pediatrics (T.M.), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to Takao Saruta, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku Tokyo 160-8582, Japan. E-mail saruta{at}sc.itc.keio.ac.jp

Angiotensin II enhances the development of atherosclerotic lesion in which cellular proliferation and/or migration are critical steps. Although cyclin-dependent kinase inhibitor, p27, and Rho/Rho-kinase pathway have recently been implicated as factors regulating these events cooperatively, their role in vivo has not been fully elucidated. We evaluated the contribution of p27 and Rho-kinase to angiotensin II-induced vascular injury using p27-deficient mice. Two-week angiotensin II (1500 ng/kg per minute SC) infusion elicited similar degrees of elevation in systolic blood pressure in wild-type mice (159±5 mm Hg) and p27-deficient mice (157±5 mm Hg; P>0.05). Angiotensin II infusion to wild-type mice resulted in increases in the medial thickness of aorta, proliferating cell number, and monocyte/macrophage infiltration within the vasculature. In p27-deficient mice, however, these changes were more prominent than those in wild-type mice. Treatment of wild-type mice with fasudil, a selective Rho-kinase inhibitor, did not alter blood pressure but significantly upregulated p27 expression, decreased medial thickness of aorta, reduced proliferating cell number, and prevented monocyte/macrophage infiltration. These protective effects of fasudil were attenuated in p27-deficient mice. In conclusion, p27 constitutes an important modulator of angiotensin II–induced monocyte/macrophage infiltration and vascular remodeling, which is mediated in part by Rho-kinase stimulation. Inhibition of Rho-kinase activity improves angiotensin II–induced vascular injury through p27-dependent and p27-independent mechanisms.

Key Words: angiotensin II • remodeling • muscle, smooth, vascular • macrophages • hypertension, experimental

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