title: Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries.
abstract: BACKGROUND
  Rho-associated kinase (ROCK), an effector of small GTPase Rho, regulates vascular tone via a calcium sensitization mechanism and plays a key role in the pathogenesis of hypertension. However, its role in vascular growth remains unclear.
  
  
  RESULTS
  Y-27632, a specific ROCK inhibitor, and the overexpression of dominant-negative ROCK suppressed the mitogen-induced DNA synthesis of cultured vascular smooth muscle cells (VSMCs), which indicates the essential role of ROCK in the control of VSMC proliferation in vitro. Y-27632 also suppressed the chemotaxis of VSMCs. Male Wistar rats were systemically given Y-27632 (35 to 70 mg. kg(-1). day(-1)) through an intraperitoneal infusion. The neointimal formation of balloon-injured carotid arteries was significantly suppressed in Y-27632-treated rats (intima/media ratio, 0.22+/-0.02) compared with vehicle-treated rats (intima/media ratio, 0.92+/-0.21) or hydralazine-treated rats with a similar blood pressure decrease (intima/media ratio, 1.03+/-0.15). The phosphorylation of myosin phosphatase and myosin light chain was elevated in injured arteries in a Y-27632-sensitive manner, indicating the augmentation of ROCK activity in neointimal formation. The downregulation of the cyclin-dependent kinase inhibitor p27(kip1) in injured vessels was reversed by Y-27632 treatment, reflecting the antiproliferative effect of ROCK inhibition in vivo.
  
  
  CONCLUSIONS
  We conclude that ROCK plays a key role in the process of neointimal formation after balloon injury. Thus, the inhibition of ROCK may be a potential therapeutic strategy for treating vascular proliferative disorders and hypertension.
authors.affiliation: Departments of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sawada
authors.forename: H
authors.initials: H
authors.lastname: Itoh
authors.forename: K
authors.initials: K
authors.lastname: Ueyama
authors.forename: J
authors.initials: J
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Doi
authors.forename: T H
authors.initials: TH
authors.lastname: Chun
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Masatsugu
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: S
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: N
authors.initials: N
authors.lastname: Ohno
authors.forename: M
authors.initials: M
authors.lastname: Komeda
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000503:physiopathology*; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development / Q000293:injuries; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases