(Circulation. 2000;101:2030.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries
From the Departments of Medicine and Clinical Science (N.S., H.I., J.Y., K.D., T.-H.C., M.I., K.M., T.S., Y.F., S.S., H.A., K.N.) and Cardiovascular Surgery (K.U., N.O., M.K.), Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Hiroshi Itoh, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp
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 p27kip1 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.
Key Words: atherosclerosis • muscle, smooth • remodeling • signal transduction • hypertension
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