title: Role of Rho-kinase and p27 in angiotensin II-induced vascular injury.
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.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku Tokyo 160-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Sugano
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mitsuhashi
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001794:Blood Pressure / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D017540:Tunica Media / Q000473:pathology; D054460:rho-Associated Kinases
chemical_list: C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil