Published Online
on February 7, 2005

A more recent version of this article appeared on April 1, 2005

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Submitted on October 7, 2004
Revised on November 1, 2004

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; and 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.

^* To whom correspondence should be addressed. E-mail: saruta{at}sc.itc.keio.ac.jp.

Abstract--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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