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

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)724-729
Number of pages6
JournalHypertension
Volume45
Issue number4 SUPPL.
DOIs
Publication statusPublished - 2005 Apr

Keywords

  • Angiotensin II
  • Hypertension, experimental
  • Macrophages
  • Muscle, smooth, vascular
  • Remodeling

ASJC Scopus subject areas

  • Internal Medicine

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