Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension
Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension
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DOI：
10.1038/40187
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发表时间：
1997-10-30
期刊：
影响因子：
64.8
通讯作者：
Narumiya, S
中科院分区：
文献类型：
--
作者：
Uehata, M;Ishizaki, T;Narumiya, S
异常的平滑肌收缩可能是高血压等疾病状态的主要原因，调节这一过程的平滑肌松弛剂在治疗上是有用的。平滑肌收缩受胞质Ca 2+浓度和肌丝Ca 2+敏感性调节（1）：前者激活肌球蛋白轻链激酶，后者部分通过抑制肌球蛋白磷酸酶实现（1-3）。小GTPase Rho及其靶点Rho相关激酶在体外参与了后一种机制（4-6），但它们的参与尚未在完整肌肉中得到证实。在这里，我们表明，吡啶衍生物，Y-27632，选择性地抑制平滑肌收缩，通过抑制Ca 2+敏化。我们将Y-27632靶点确定为Rho相关蛋白激酶p160 ROCK（7）。Y-27632一贯抑制Rho诱导的，p160 ROCK介导的应力纤维在培养细胞中的形成，并显着纠正高血压大鼠模型中的高血压。我们的研究结果表明，p160 ROCK介导的Ca 2+敏化参与高血压的病理生理学，并建议抑制这一过程的化合物可能是有用的治疗。
Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments(1): the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase(1-3). The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro(4-6), but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK(7). Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.