Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil.
Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil.
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DOI：
10.1097/fjc.0b013e3182a3718f
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发表时间：
2013-10
影响因子：
3
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Shi J;Wei L
Rho 激酶 (ROCK) 是小 GTP 酶 RhoA 的主要下游效应器。 ROCK家族由ROCK1和ROCK2组成，在肌动蛋白细胞骨架的组织中发挥核心作用，并参与广泛的基本细胞功能，例如收缩、粘附、迁移、增殖和凋亡。由于法舒地尔和 Y27632 等有效抑制剂的发现，ROCK 的生物学作用已得到广泛探索，特别关注心血管系统。在许多心血管疾病的临床前模型中，包括血管痉挛、动脉硬化、高血压、肺动脉高压、中风、缺血再灌注损伤和心力衰竭，ROCK抑制剂在减少血管平滑肌细胞过度收缩、内皮功能障碍、炎症细胞募集、血管重塑和心脏重塑方面表现出显着功效。此外，法舒地尔已用于多种心血管疾病的临床试验。在 ROCK 信号传导研究和人类疾病治疗中，现有药理学抑制剂的持续利用以及更有效或异构体选择性抑制剂的开发正在不断升级。在这篇综述中，我们讨论了最近的分子、细胞、动物和临床研究，重点是当前对心血管生理学和疾病中 ROCK 信号传导的理解。我们特别注意到，新出现的证据表明，基于疾病病理生理学的选择性靶向 ROCK 同工型可能代表了包括心血管疾病在内的疾病治疗的一种新的治疗方法。
Rho kinase (ROCK) is a major downstream effector of the small GTPase RhoA. ROCK family, consisting of ROCK1 and ROCK2, plays central roles in the organization of actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Due to the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored with particular attention on the cardiovascular system. In many preclinical models of cardiovascular diseases including vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, stroke, ischemia-reperfusion injury and heart failure, ROCK inhibitors have shown a remarkable efficacy in reducing vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment, vascular remodeling, and cardiac remodeling. Moreover, fasudil has been used in the clinical trials of several cardiovascular diseases. The continuing utilization of available pharmacological inhibitors and the development of more potent or isoform-selective inhibitors in ROCK signaling research and in treating human diseases are escalating. In this review, we discuss the recent molecular, cellular, animal and clinical studies with a focus on the current understanding of ROCK signaling in cardiovascular physiology and diseases. We particularly note that emerging evidence suggests that selective targeting ROCK isoform based on the disease pathophysiology may represent a novel therapeutic approach for the disease treatment including cardiovascular diseases.