Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries

Naoki Sawada, Hiroshi Itoh, Koji Ueyama, Jun Yamashita, Kentaro Doi, Tae Hwa Chun, Mayumi Inoue, Ken Masatsugu, Takatoshi Saito, Yasutomo Fukunaga, Satsuki Sakaguchi, Hiroshi Arai, Nobuhisa Ohno, Masashi Komeda, Kazuwa Nakao

Research output: Contribution to journalArticle

176 Citations (Scopus)

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. Methods and 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.

Original languageEnglish
Pages (from-to)2030-2033
Number of pages4
JournalCirculation
Volume101
Issue number17
Publication statusPublished - 2000 May 2
Externally publishedYes

Fingerprint

rho-Associated Kinases
Arteries
Vascular Smooth Muscle
Smooth Muscle Myocytes
Blood Vessels
Myosin-Light-Chain Phosphatase
Parenteral Infusions
Cyclin-Dependent Kinase Inhibitor p27
Hypertension
Hydralazine
Myosin Light Chains
Monomeric GTP-Binding Proteins
Inhibition (Psychology)
Chemotaxis
Mitogens
Carotid Arteries
Y 27632
Wistar Rats
Down-Regulation
Phosphorylation

Keywords

  • Atherosclerosis
  • Hypertension
  • Muscle, smooth
  • Remodeling
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Sawada, N., Itoh, H., Ueyama, K., Yamashita, J., Doi, K., Chun, T. H., ... Nakao, K. (2000). Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation, 101(17), 2030-2033.

Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. / Sawada, Naoki; Itoh, Hiroshi; Ueyama, Koji; Yamashita, Jun; Doi, Kentaro; Chun, Tae Hwa; Inoue, Mayumi; Masatsugu, Ken; Saito, Takatoshi; Fukunaga, Yasutomo; Sakaguchi, Satsuki; Arai, Hiroshi; Ohno, Nobuhisa; Komeda, Masashi; Nakao, Kazuwa.

In: Circulation, Vol. 101, No. 17, 02.05.2000, p. 2030-2033.

Research output: Contribution to journalArticle

Sawada, N, Itoh, H, Ueyama, K, Yamashita, J, Doi, K, Chun, TH, Inoue, M, Masatsugu, K, Saito, T, Fukunaga, Y, Sakaguchi, S, Arai, H, Ohno, N, Komeda, M & Nakao, K 2000, 'Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries', Circulation, vol. 101, no. 17, pp. 2030-2033.
Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun TH et al. Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation. 2000 May 2;101(17):2030-2033.
Sawada, Naoki ; Itoh, Hiroshi ; Ueyama, Koji ; Yamashita, Jun ; Doi, Kentaro ; Chun, Tae Hwa ; Inoue, Mayumi ; Masatsugu, Ken ; Saito, Takatoshi ; Fukunaga, Yasutomo ; Sakaguchi, Satsuki ; Arai, Hiroshi ; Ohno, Nobuhisa ; Komeda, Masashi ; Nakao, Kazuwa. / Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. In: Circulation. 2000 ; Vol. 101, No. 17. pp. 2030-2033.
@article{a180a7c9db19414297ff43877fb143f3,
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. Methods and 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.",
keywords = "Atherosclerosis, Hypertension, Muscle, smooth, Remodeling, Signal transduction",
author = "Naoki Sawada and Hiroshi Itoh and Koji Ueyama and Jun Yamashita and Kentaro Doi and Chun, {Tae Hwa} and Mayumi Inoue and Ken Masatsugu and Takatoshi Saito and Yasutomo Fukunaga and Satsuki Sakaguchi and Hiroshi Arai and Nobuhisa Ohno and Masashi Komeda and Kazuwa Nakao",
year = "2000",
month = "5",
day = "2",
language = "English",
volume = "101",
pages = "2030--2033",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",

}

TY - JOUR

T1 - Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries

AU - Sawada, Naoki

AU - Itoh, Hiroshi

AU - Ueyama, Koji

AU - Yamashita, Jun

AU - Doi, Kentaro

AU - Chun, Tae Hwa

AU - Inoue, Mayumi

AU - Masatsugu, Ken

AU - Saito, Takatoshi

AU - Fukunaga, Yasutomo

AU - Sakaguchi, Satsuki

AU - Arai, Hiroshi

AU - Ohno, Nobuhisa

AU - Komeda, Masashi

AU - Nakao, Kazuwa

PY - 2000/5/2

Y1 - 2000/5/2

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - Atherosclerosis

KW - Hypertension

KW - Muscle, smooth

KW - Remodeling

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=0342314481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0342314481&partnerID=8YFLogxK

M3 - Article

C2 - 10790342

AN - SCOPUS:0342314481

VL - 101

SP - 2030

EP - 2033

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -