Rho/ROCK信号通路在慢性充血性心力衰竭中的作用

Rho/Rho相关的卷曲蛋白激酶（ROCK）信号通路的关键信号分子包括Rho、ROCK及其主要效应分子肌球蛋白轻链磷酸酶（MLCP）、肌球蛋白轻链激酶（MLCK）、肌球蛋白轻链（MLC）等,该信号通路激活后可产生多种生物效应,如肌动蛋白细胞骨架形成、细胞收缩、钙敏化等,且这些效应与心力衰竭的发展过程有关.目前,对于Rho/ROCK信号通路的研究主要集中在心、脑血管系统中,如缺血性卒中、高血压、冠心病等.越来越多的研究表明,Rho/ROCK信号通路的关键分子在慢性充血性心力衰竭（CHF）中存在异常表达与活化,提示该信号转导通路在CHF发病机制中具有重要的作用.本文结合文献就Rho/ROCK信号通路在CHF过程中对细胞舒缩功能、交感兴奋、细胞凋亡等的作用综述如下.     

Rho／ROCK信号转导通路与支气管哮喘气道重塑

支气管哮喘（简称哮喘）是多种细胞及其组分参与的慢性非特异性炎症性疾病,气道反复炎症损伤与修复造成的气道重塑是哮喘主要的病理生理学特征,预防气道重塑是哮喘干预治疗的重要潜在靶点,是改善哮喘预后的重要手段。Rho通过激活下游效应物Rho相关卷曲螺旋形成蛋白激酶（Rho associated coiled coil forming protein kinase,ROCK）作用于气道平滑肌细胞及调节细胞因子和炎性因子等的产生,在哮喘气道重塑的形成与发展中起关键的作用,ROCK抑制剂能有效抑制哮喘动物模型的气道炎症和气道重塑作用。     

Rho/ROCK信号转导通路与支气管哮喘气道重塑

支气管哮喘(简称哮喘)是多种细胞及其组分参与的慢性非特异性炎症性疾病,气道反复炎症损伤与修复造成的气道重塑是哮喘主要的病理生理学特征,预防气道重塑是哮喘干预治疗的重要潜在靶点,是改善哮喘预后的重要手段.Rho通过激活下游效应物Rho相关卷曲螺旋形成蛋白激酶(Rho associated coiled coil fotruing protein kinase,ROCK)作用于气道平滑肌细胞及调节细胞因子和炎性因子等的产生,在哮喘气道重塑的形成与发展中起关键的作用,ROCK抑制剂能有效抑制哮喘动物模型的气道炎症和气道重塑作用.     

Rho/Rho激酶信号通路与糖尿病肾病

糖尿病肾病(DN)是糖尿病重要的微血管并发症之一,其发病机制是多种因素共同作用的结果.近年来发现Rho/Rho激酶(Rho/ROCK)信号通路与多种组织重构如血管、心肌、肾纤维化等相关.高糖能够刺激肾脏细胞内Rho/ROCK信号通路的激活,后者通过调控转录因子的DNA结合活性上调多种基因的表达,从而引起各种炎性反应及肾小球纤维化,而应用此信号通路选择性抑制剂后可明显改善DN的发生和发展,从而认为Rho/ROCK信号转导通路可能在DN的发病机制中起关键作用.     

Rho相关蛋白激酶与动脉粥样硬化关系的研究进展

<正>动脉粥样硬化(AS)是一种累及全身大血管壁的慢性炎性反应和脂质沉积过程,一些危险因素(如高血糖、血脂异常以及高血压等)可以激活多种信号通路参与AS的发展,Rho A/Rho相关蛋白激酶(ROCK)通路就是其中之一。越来越多的证据表明,RhoA/ROCK通路参与AS过程的许多步骤,ROCK可能成为AS的潜在治疗靶点,了解Rho/ROCK通路在AS进展过程中的作用对AS的防治有重要意义^[1]。     

Ras同源基因家族蛋白A/Rho相关卷曲螺旋蛋白激酶抑制剂对冠状动脉微栓塞引起心肌损伤的预防作用

目的:探讨Ras同源基因家族蛋白A(Rho A)/Rho相关卷曲螺旋蛋白激酶(ROCK)信号通路在冠状动脉微栓塞(CME)大鼠心肌凋亡的作用机制。方法:将60只SD大鼠随机分为3组:假手术组、模型组、抑制剂组;模型组、抑制剂组经左心室注入微栓塞球构建CME模型;构建CME模型前1 h抑制剂组尾静脉注射Rho A/Rho信号通路抑制剂(Y-27632)(5 mg/kg)。术后12 h依次采用:苏木素碱性品红苦味酸(HBFP)染色、脱氧核糖核苷酸末端转移酶介导的缺口末端标记(TUNEL)染色、免疫印迹法(Western blot)检测心肌缺血微梗死面积、心肌细胞的凋亡率以及p-Rho A、ROCK1、ROCK2的表达水平。结果:与假手术组相比,模型组大鼠心脏的微梗死面积、心肌细胞凋亡率、p-Rho A、ROCK1、ROCK2的表达明显升高,与模型组相比,抑制剂组大鼠的心脏的微梗死面积、心肌细胞凋亡率、p-Rho A、ROCK1、ROCK2的表达明显降低,差异均有统计学意义(均P0.05)。结论:CME激活Rho A/ROCK通路,抑制Rho A/ROCK通路能明显降低心肌的凋亡率,改善CME大鼠心功能。     

支气管哮喘患者Rho激酶信号通道与T调节细胞的相关性

支气管哮喘（简称哮喘）被认为是一种气道慢性非特异性炎症性疾病,许多细胞因子和炎症介质参与了这个病理生理过程。目前研究显示,Rho激酶信号通道及T调节细胞在哮喘的发病机制中起重要作用,而他汀类药物也具有抑制促炎性细胞因子和细胞因子的分泌,增加调节性T细胞数量和功能等作用。本文就哮喘中Rho激酶信号转导通路与调节T细胞的相关性进行简要综述。     

Ras同源基因家族蛋白A/Rho相关卷曲螺旋蛋白激酶信号通路与脑梗死关系的研究进展

<正>Ras同源基因家族蛋白A(Ras homolog gene family member A,Rho A)/Rho相关卷曲螺旋蛋白激酶(Rho-associated coiled-coil forming protein kinase,ROCK)信号通路参与许多细胞的调控过程,包括转录、细胞骨架的改变、收缩、黏附、运动、增殖、分化等,同时其与动脉粥样硬化、脑梗死、缺血-再灌注损伤的发生发展密切相关~([1])。通过抑制Rho A/ROCK信号通路的激活治疗脑梗死的相关基础和临床研究成为热点,笔者就Rho A/ROCK信号通路与脑梗死     

Rho/Rho激酶信号通路与糖尿病肾病

糖尿病肾病(DN)是糖尿病重要的微血管并发症之一,其发病机制是多种因素共同作用的结果.近年来发现Rho/Rho激酶(Rho/ROCK)信号通路与多种组织重构如血管、心肌、肾纤维化等相关.高糖能够刺激肾脏细胞内Rho/ROCK信号通路的激活,后者通过调控转录因子的DNA结合活性上调多种基因的表达,从而引起各种炎性反应及肾...     

Rho激酶与心血管疾病

<正>1996年,人们发现Rho激酶(Rho associated kinase,ROCK)是Rho的下游效应器之一,随着研究的深入,发现其参与了血管平滑肌细胞、内皮细胞、外膜细胞、心肌细胞的形态、收缩、迁移、增殖、凋亡、基因转录等多种病理生理改变,它的异常活化与心血管疾病的发病机制密切相关。近年来关于ROCK的研究主要集中在心血管系统方面,主要因为:(1)Rho/ROCK通路参与的各种细胞功能在心血管疾病的发     

Therapeutic potentials of the Rho kinase inhibitor Fasudil in experimental autoimmune encephalomyelitis and the related mechanisms

Multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.

     

RhoA/ROCK signaling pathway and astrocytes in ischemic stroke

Ischemic stroke is one of the most common and undertreated cerebral diseases with high mortality and disability rate. Various intrinsic and extrinsic factors regulate the onset, severity, and progression of ischemic stroke. As an integral part of the neuronal glia system, astrocytes provide many housekeeping functions in nervous system, and perform multiple functions both beneficial and detrimental for neuronal survival after ischemic stroke. In addition, the small GTPase Rho and its downstream Rho kinase (ROCK) are associated with various neuronal functions such as dendrite development, migration and axonal extension, and numerous central nervous system (CNS) diseases. The aim of this review is to summarize the role of RhoA/ROCK signaling pathway and astrocytes on neurological function after ischemic stroke. We also discuss the interaction of RhoA/ROCK signaling pathway and astrocytes on the tissue repair after brain injury.

     

Rho kinase as a therapeutic target in cardiovascular disease

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 and 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 and chemical inhibitors (e.g., Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Extensive experimental and 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.     

Rho/ROCK与神经系统疾病

作为一种分子开关,Rho可在无活性的GDP结合形式和有活性的GTP结合形式之间转换,传递信号给下游底物Rho激酶(ROCK),介导特殊的生物学效应,参与多种神经系统疾病,如缺血性卒中、脑血管痉挛、脊髓损伤后轴突再生的病理学过程.应用ROCK抑制剂治疗神经系统疾病已取得满意效果.Rho/ROCK有望成为一个新的治疗靶点.     

Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition

The Rho/ROCK pathway is activated in differentiated hepatic stellate cells (HSCs) and is necessary for assembly of actin stress fibers, contractility, and chemotaxis. Despite the importance of this pathway in HSC biology, physiological inhibitors of the Rho/ROCK pathway in HSCs are not known. We demonstrate that adenosine induces loss of actin stress fibers in the LX-2 cell line and primary HSCs in a manner indistinguishable from Rho/ROCK inhibition. Loss of actin stress fibers occurs via the A2a receptor at adenosine concentrations above 10 muM, which are present during tissue injury. We further demonstrate that loss of actin stress fibers is due to a cyclic adenosine monophosphate, protein kinase A-mediated pathway that results in Rho inhibition. Furthermore, a constitutively active Rho construct can inhibit the ability of adenosine to induce loss of actin stress fibers. Actin stress fibers are required for HSC contraction, and we demonstrate that adenosine inhibits endothelin-1 and lysophosphatidic acid-mediated HSC contraction. We propose that adenosine is a physiological inhibitor of the Rho pathway in HSCs with functional consequences, including loss of HSC contraction.     

Rho激酶在心血管疾病中新进展及Rho激酶抑制剂的应用

Rho激酶(ROCK)被认为是治疗心血管疾病的新靶点。本文主要简述RhoA/ROCK通路在调节脉管系统的功能,并探讨其在心血管疾病发病中的作用机制。     

Rho/ROCK signaling in motility and metastasis of gastric cancer

Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases (ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition, the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility, there are two modes of tumor cell movement: mesenchymal and amoeboid. In addition, cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer. In addition, we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway.     

ROCK抑制剂治疗心血管疾病的研究进展

ROCK为Rho相关的卷曲蛋白激酶,其表达上调常引起平滑肌细胞收缩异常,导致冠状动脉痉挛、动脉粥样硬化、心肌肥厚和肺动脉高压等,因此ROCK抑制剂对这些心血管疾病的发生发展有一定抑制作用,但临床应用尚需更多的研究来证实,本文就ROCK抑制剂在心血管疾病的应用作一综述。