Rho kinase as a therapeutic target in cardiovascular disease.
Rho kinase as a therapeutic target in cardiovascular disease.
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DOI：
10.2217/fca.11.51
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发表时间：
2011-09
影响因子：
1.7
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Surma M;Wei L;Shi J
Rho激酶(ROCK)属于丝氨酸/苏氨酸激酶AGC(PKA/PKG/PKC)家族，是小分子GTP酶RhoA的主要下游效应因子。ROCK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，如收缩、黏附、迁移、增殖和基因表达。两种ROCK亚型，ROCK1和ROCK2，被认为是功能冗余的，主要是基于主要的共同激活物，在激酶结构域内的高度同源性，以及从过度表达与激酶的研究构建了一种化学抑制剂(例如，Y27632a和d Fasudil)，它同时抑制ROCK1和ROCK2。广泛的实验和临床研究支持RhoA/ROCK通路在心血管疾病发病机制中的关键作用，其中ROCK活性增加介导血管平滑肌细胞过度收缩、内皮功能障碍、炎性细胞募集和血管重塑。最近使用ROCK抑制剂或遗传小鼠模型的实验研究表明，心肌中的RhoA/ROCK通路参与了缺血损伤或持续肥厚应激诱导的心脏重构，从而导致心脏失代偿和心力衰竭。本文基于最新的分子、细胞和动物研究，重点介绍ROCK信号在心血管疾病和心力衰竭发病机制中的研究现状。
Rho kinase (ROCK) belongs to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and is a major downstream effector of the small GTPase RhoA. ROCK plays central roles in the organization of the actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation and gene expression. Two ROCK isoforms, ROCK1 a n d ROCK2, are assumed to be functionally redundant, based largely on the major common activators, the high degree of homology within the kinase domain and studies from overexpression with kinase constructs a n d chemical inhibitors (e.g., Y27632 a n d fasudil), which inhibit both ROCK1 and ROCK2. Extensive experimental a n d clinical studies support a critical role for the RhoA/ROCK pathway in the vascular bed in the pathogenesis of cardiovascular diseases, in which increased ROCK activity mediates vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment and vascular remodeling. Recent experimental studies, using ROCK inhibitors or genetic mouse models, indicate that the RhoA/ROCK pathway in myocardium contributes to cardiac remodeling induced by ischemic injury or persistent hypertrophic stress, thereby leading to cardiac decompensation and heart failure. This article, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in cardiovascular diseases and in the pathogenesis of heart failure.