Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun T H, Inoue M, Masatsugu K, Saito T, Fukunaga Y, Sakaguchi S, Arai H, Ohno N, Komeda M, Nakao K
Departments of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Circulation. 2000 May 2;101(17):2030-3. doi: 10.1161/01.cir.101.17.2030.
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.
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.
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.
Rho相关激酶（ROCK）是小GTP酶Rho的效应器，通过钙敏化机制调节血管张力，在高血压发病机制中起关键作用。然而，其在血管生长中的作用尚不清楚。
特异性ROCK抑制剂Y-27632以及显性负性ROCK的过表达抑制了丝裂原诱导的培养血管平滑肌细胞（VSMC）的DNA合成，这表明ROCK在体外控制VSMC增殖中起重要作用。Y-27632还抑制了VSMC的趋化性。通过腹腔内输注给雄性Wistar大鼠全身给予Y-27632（35至70mg·kg⁻¹·天⁻¹）。与载体处理的大鼠（内膜/中膜比值，0.92±0.21）或血压下降相似的肼屈嗪处理的大鼠（内膜/中膜比值，1.03±0.15）相比，Y-27632处理的大鼠球囊损伤颈动脉的新生内膜形成明显受到抑制（内膜/中膜比值，0.22±0.02）。肌球蛋白磷酸酶和肌球蛋白轻链的磷酸化在损伤动脉中以Y-27632敏感的方式升高，表明ROCK活性在新生内膜形成中增强。Y-27632处理可逆转损伤血管中细胞周期蛋白依赖性激酶抑制剂p27kip1的下调，反映了ROCK抑制在体内的抗增殖作用。
我们得出结论，ROCK在球囊损伤后的新生内膜形成过程中起关键作用。因此，抑制ROCK可能是治疗血管增殖性疾病和高血压的潜在治疗策略。
