Rho激酶与呼吸系统疾病

Rho/Rho激酶通过GDP-Rho与GTP-Rho之间的转换调节细胞的收缩、黏附、增殖、迁徙、凋亡等生物学行为.目前一系列研究已证实Rho/Rho激酶信号通路参与了许多呼吸系统疾病的发生、发展,如慢性阻塞性肺疾病、支气管哮喘、肺高压、特发性肺纤维化、肺癌等.本文旨在讨论Rho激酶在呼吸系统疾病中的作用及相关机制.     

Rho/Rho激酶信号通路与冠心病

Rho/Rho激酶信号通路是体内普通存在的一条信号转导通路,它通过调节细胞内肌动蛋白骨架的聚合状态参与多种细胞功能,包括细胞收缩、迁移、黏附、增殖、凋亡及基因表达等。Rho/Rho激酶信号通路的异常激活在冠心病的发病机制和病理生理中发挥了重要作用,对此信号转导通路的研究可以为冠心病的预防和治疗提供新的靶点。现就Rho/Rho激酶信号通路的特征及其与冠心病的关系作一综述。     

Rho/Rho激酶信号通路与缺血性脑血管病

Rho/Rho激酶信号通路是体内普遍存在的一条信号通路,它通过调节细胞内肌动蛋白骨架的聚合状态而扮演着"分子开关"角色,参与多种细胞功能.Rho/Rho激酶信号通路在缺血性脑血管病的危险因素、发病机制和病理生理学过程中发挥着重要作用,抑制Rho/Rho激酶信号通路能够取得显著的神经保护作用.     

Rho/Rho激酶与动脉粥样硬化的研究进展

<正> 随着对促动脉粥样硬化因子的深入研究,Rho/Rho激酶途径逐渐受到人们的关注。现已发现,Rho/Rho激酶参与细胞黏附、迁移、平滑肌细胞收缩及胞质分裂等的调节,而这些细胞功能均参与了动脉粥样硬化的发生与发展。动物实验及临床研究均证明,Rho/Rho激酶与动脉粥样硬化、高血压、心肌缺血等心血管疾病的发病过程相关。因此,对     

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/Rho激酶信号通路与缺氧性肺动脉高压

缺氧性肺动脉高压(hypoxic pulmonaryhypertension,HPH)是一些先天性心血管疾病和慢性肺部疾病最常见的并发症,以肺血管收缩反应性增强和肺血管结构重构为特征,其发生机制尚未完全清楚。近年来研究表明,Rho/Rho激酶信号通路在急性缺氧性肺血管收缩和慢性缺氧引起的肺动脉高压和肺血管结构重构过程中发挥重要作用。1 Rho/Rho激酶信号通路的生物学特征Rho/Rho激酶信号转导通路的关键信号分子包括Rho蛋白、Rho激酶和肌球蛋白磷酸酶。Rho蛋白为小分子鸟苷酸结合蛋白(又称小G蛋白),是Ras蛋白超家族成员。在哺乳动物细胞内有RhoA、RhoB、R…     

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激酶抑制剂保护心肌缺血再灌注损伤的研究

Rho蛋白通过Rho/ROCK信号途径发挥各种生物效应并广泛参与各种生命活动过程,如平滑肌细胞收缩,调节细胞骨架组装,细胞凋亡等过程。近年来研究发现该信号途径与许多心血管疾病如冠心病,高血压,肺动脉高压等疾病的发生发展关系密切。研究表明ROCK蛋白也参与心肌缺血再灌注损伤过程。该文就Rho及其信号通路的生物学特性及在急性心肌缺血再灌注损伤过程中病理生理机制研究及临床应用前景作简要的综述。     

Rho/Rho激酶信号通路与高血压

1985年,Rho作为Ras同源物首先被克隆出来,此后的研究发现Rho作为信号调节分子联系细胞表面受体与肌动蛋白细胞骨架的组建,在细胞代谢过程中发挥重要作用.近年来,一系列研究显示Rho/Rho激酶信号通路主要通过磷酸化抑制肌球蛋白轻链磷酸酶(myosin light chain phosphase,MLCP)的活性来增加肌球蛋白轻链(myosin lightchain,MLC)的磷酸化水平,从而增强平滑肌的收缩力,在高血压的发生和发展中起着非常重要的作用.     

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-kinase is an important therapeutic target in cardiovascular medicine

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.     

Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats

Chronic inhibition of endothelial NO synthesis by the administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 expression) as well as subsequent arteriosclerosis. The small GTPase Rho controls cell adhesion, motility, and proliferation and is activated by several growth factors such as angiotensin II. We investigated the effect of a specific inhibitor of Rho-kinase, Y-27632, in rats treated with L-NAME to determine the role of the Rho/Rho-kinase pathway in the development of arteriosclerosis. We found here increased activity of Rho/Rho-kinase after L-NAME administration and its prevention by angiotensin II type 1 receptor blockade. Hydralazine or lecithinized superoxide dismutase (l-SOD) did not affect Rho/Rho-kinase activity. Co-treatment with Y-27632 did not affect the L-NAME-induced increase in cardiovascular tissue ACE activity or L-NAME-induced decrease in plasma NO concentrations, but did prevent the L-NAME-induced early inflammation and late coronary arteriosclerosis. In addition, Y-27632 prevented the increased gene expression of monocyte chemoattractant protein-1 and transforming growth factor-beta1 as well as cardiac fibrosis and glomerulosclerosis. These findings suggest that increased activity of Rho/Rho-kinase pathway mediated via the angiotensin II type 1 receptor may thus be important in the pathogenesis of early vascular inflammation and late remodeling induced by chronic inhibition of NO synthesis. The beneficial effects of Rho-kinase inhibition are not mediated by restoration of NO production. The Rho-kinase pathway could be a new therapeutic target for treatment of vascular diseases.     

活性氧簇在低氧诱导的肺纤维化中的作用

活性氧簇是一类氧的衍生分子,因其可引起蛋白质、DNA等大分子物质损伤、脂质过氧化,一直被认为是有害因子.近年来研究表明活性氧簇的产生是受精细调节的,并且它能作为第二信使激活细胞内MAPK(ERK1/2、p38MAPK和JNK)、Akt/PKB、JAK-STAT、核因子κB等多条信号通路,参与转化生长因子β1、血小板衍生生长因子、缺氧诱导因子、结缔组织生长因子等多种致纤维化因子的信号转导,调节细胞的增殖、分化、凋亡等生理功能,并与动脉粥样硬化、肝纤维化、肺纤维化等疾病的发生有关.低氧是一个重要的病理过程,可引起细胞损伤、组织炎细胞浸润,并能促进上皮细胞向间质细胞转化、细胞外基质沉积,上调转化生长因子β1、血小板衍生生长因子、缺氧诱导因子、结缔组织生长因子等多种致纤维化因子,故低氧有诱导肺纤维化形成的可能.而低氧又可引起活性氧簇产生增多.本文就活性氧簇在低氧诱导的肺纤维化中的作用作一综述.     

Long-term diabetic complications may be ameliorated by targeting Rho kinase

This review addresses the roles of Rho/Rho-kinase (ROCK) pathway in the pathogenesis of diabetes complications. Diabetes can cause many serious complications and can result in physical disability or even increased mortality. However, there are not many effective ways to treat these complications. The small guanosine-5'-triphosphate-binding protein Rho and its downstream target Rho-kinase mediate important cellular functions, such as cell morphology, motility, secretion, proliferation, and gene expression. Recently, the Rho/Rho-kinase pathway has attracted a great deal of attention in diabetes-related research. These studies have provided evidence that the activity and gene expression of Rho-kinase are upregulated in some tissues in animal models of type 1 or type 2 diabetes and in cell lines cultured with high concentrations of glucose. Inhibitors of Rho-kinase could prevent or ameliorate the pathological changes in diabetic complications. The inhibitory effects of statins on the Rho/Rho-kinase signalling pathway may also play a role in the prevention of diabetic complications. However, the precise molecular mechanism by which the Rho/Roh-kinase pathway participates in the development or progression of diabetic complications has not been extensively investigated. This article evaluates the relationship between Rho/Roh-kinase activation and diabetic complications, as well as the roles of Roh-kinase inhibitors and statins in the complications of diabetes, with the objective of providing a novel target for the treatment of long-term diabetic complications.     

Role of Rho GTPases in thrombin-induced lung vascular endothelial cells barrier dysfunction

Thrombin-induced barrier dysfunction of pulmonary endothelial monolayer is associated with dramatic cytoskeletal reorganization, activation of actomyosin contraction, and gap formation. Phosphorylation of regulatory myosin light chains (MLC) is a key mechanism of endothelial cell (EC) contraction and barrier dysfunction, which is triggered by Ca(2+)/calmodulin-dependent MLC kinase (MLCK) and Rho-associated kinase (Rho-kinase). The role of MLCK in EC barrier regulation has been previously described; however, Rho-mediated pathway in thrombin-induced pulmonary EC dysfunction is not yet precisely characterized. Here, we demonstrate that thrombin-induced decreases in transendothelial electrical resistance (TER) indicating EC barrier dysfunction are universal for human and bovine pulmonary endothelium, and involve membrane translocation and direct activation of small GTPase Rho and its downstream target Rho-kinase. Transient Rho membrane translocation coincided with translocation of upstream Rho activator, guanosine nucleotide exchange factor p115-RhoGEF. Rho mediated activation of downstream target, Rho-kinase induced phosphorylation of the EC MLC phosphatase (MYPT1) at Thr(686) and Thr(850), resulting in MYPT1 inactivation, accumulation of diphospho-MLC, actin remodeling, and cell contraction. The specific Rho-kinase inhibitor, Y27632, abolished MYPT1 phosphorylation, MLC phosphorylation, significantly attenuated stress fiber formation and thrombin-induced TER decrease. Furthermore, expression of dominant-negative Rho and Rho-kinase abolished thrombin-induced stress fiber formation and MLC phosphorylation. Our data, which provide comprehensive analysis of Rho-mediated signal transduction in pulmonary EC, demonstrate involvement of guanosine nucleotide exchange factor, p115-RhoGEF, in thrombin-mediated Rho regulation, and suggest Rho, Rho-kinase, and MYPT1 as potential pharmacological and gene therapy targets critical for prevention of thrombin-induced EC barrier disruption and pulmonary edema associated with acute lung injury.     

Key role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in pulmonary vascular remodeling and vascular angiogenesis associated with hypoxic pulmonary hypertension

We have found that 15-hydroxyeicosatetraenoic acid (15-HETE) induced by hypoxia was an important mediator in the regulation of hypoxic pulmonary hypertension, including the pulmonary vasoconstriction and remodeling. However, the underlying mechanisms of the remodeling induced by 15-HETE are poorly understood. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and tube formation, pulmonary artery smooth muscle cells bromodeoxyuridine incorporation, and cell cycle analysis to determine the role of 15-HETE in hypoxia-induced pulmonary vascular remodeling. We found that hypoxia induced pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis, which were mediated by 15-HETE. Moreover, 15-HETE regulated the cell cycle progression and made more smooth muscle cells from the G(0)/G(1) phase to the G(2)/M+S phase and enhanced the microtubule formation in cell nucleus. In addition, we found that the Rho-kinase pathway was involved in 15-HETE-induced endothelial cells tube formation and migration and smooth muscle cell proliferation. Together, these results show that 15-HETE mediates hypoxia-induced pulmonary vascular remodeling and stimulates angiogenesis via the Rho-kinase pathway.     

Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation

Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase-dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.