1. Role of Rho-kinase and p27 in angiotensin II-induced vascular injury.
- Author
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Kanda T, Hayashi K, Wakino S, Homma K, Yoshioka K, Hasegawa K, Sugano N, Tatematsu S, Takamatsu I, Mitsuhashi T, and Saruta T
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Animals, Aorta, Abdominal drug effects, Blood Pressure drug effects, Cell Cycle Proteins antagonists & inhibitors, Cell Proliferation drug effects, Cyclin-Dependent Kinase Inhibitor p27, Intracellular Signaling Peptides and Proteins, Macrophages pathology, Male, Mice, Mice, Knockout, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins deficiency, Tunica Media pathology, rho-Associated Kinases, Angiotensin II pharmacology, Aorta, Abdominal metabolism, Aorta, Abdominal pathology, Cell Cycle Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism
- 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.
- Published
- 2005
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