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激酶信号通路与低氧所致肺纤维化

小G蛋白Rho参与了细胞黏附、迁移、生长、细胞收缩及细胞分裂等多种生物学行为.近来研究显示Rho/Rho激酶信号通路的异常活化参与了肺部疾病的发生,如肺动脉高压和肺纤维化.低氧作为一种潜在的促纤维化因素主要通过促内皮细胞凋亡、血管生成及炎症反应的调节来参与纤维化的发生.且Rho/Rho激酶信号通路与低氧所致肺纤维化的过程中所涉及主要细胞因子都有着直接或IhJ接的关系.因此,本文就Rho/Rho激酶信号通路的生物学特征及其与低氧致肺纤维化过程中细胞凶子的关系作一综述.     

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/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激酶抑制剂在心血管疾病中的应用

Rho激酶通路参与了多种心血管疾病发病的病理生理机制,Rho激酶抑制剂具有抗血管痉挛和抗动脉硬化等作用,因此,Rho激酶通路或许是心血管疾病一种新的治疗靶点。     

抑制Rho/Rho激酶信号对动脉粥样硬化大鼠心血管系统的保护作用

目的探讨抑制Rho/Rho激酶信号对动脉粥样硬化(AS)过程中心血管系统的保护作用。方法实验设置对照组、模型组、Y-27632低剂量组、Y-27632高剂量组,采用高脂饮食配合钙超载的方法建立大鼠AS模型,并给予Y-27632抑制Rho/Rho激酶信号通路。末次给药后颈动脉取血检测血清TC、HDL,HE染色检测心肌组织病理改变,Western blot法检测肌球蛋白磷酸酶抗体(MYPT-1)磷酸化情况,RT-PCR检测内皮型一氧化氮合酶(eNOS)、I型纤溶酶原激活物抑制物(PAI-1)的表达。结果模型组大鼠血清HDL含量降低(P<0.05),TC、AS指数升高(P均<0.05),心肌松散、细胞排列紊乱;与模型组相比,Y-27632低、高剂量组TC含量以及AS指数降低(P均<0.05),心肌组织状态得到明显恢复;模型组MYPT-1磷酸化水平以及PAI-1 mRNA的表达升高(P均<0.05),而与模型组相比Y-27632低、高剂量组显著降低(P均<0.05);模型组eNOS mRNA表达显著降低(P<0.05),与模型组相比Y-27632低、高剂量组显著升高(P均<0.05)。结论采用Y-27632抑制Rho/Rho激酶信号通路,能够减缓AS进程从而保护心血管系统。     

Rho/Rho激酶与缺血性脑卒中

Rho／Rho激酶是具有信息传导和分子开关功能的信号多肽，多种病理因素可使中枢神经系统等组织内Rho激酶异常激活。在神经系统，异常激活的Rho／Rho激酶与血管痉挛、缺血性神经元损伤密切相关，通过多种途径参与缺血性脑卒中的病理过程。本研究阐述缺血性脑卒中发病过程中，Rho／Rho激酶可能作用机制及Rho激酶抑制剂在缺血性脑卒中的应用。     

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 light chain，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激酶与支架内再狭窄

目的 支架内再狭窄与血管平滑肌分化、迁移,细胞外基质的过度增值所致新生内膜增生密切相关.Rho激酶参与支架置入引起的新生内膜增生的调节.长期抑制Rho激酶的表达可阻止新生内膜的增生,可能成为防止支架内再狭窄的一种方法.     

Rho/Rho-kinase pathway in brain stem contributes to blood pressure regulation via sympathetic nervous system: possible involvement in neural mechanisms of hypertension

Recent studies have demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, including actin cytoskeleton organization and vascular smooth muscle contraction. This pathway is also present in the central nervous system and is involved in the maintenance of dendritic spines and axon outgrowth and in the regulation of neurotransmitter release. However, its role in central blood pressure regulation is unknown. In the present study, blockade of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem by microinjection of a specific Rho-kinase inhibitor decreased blood pressure, heart rate, and renal sympathetic nerve activity in both Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). However, the magnitude of decreases in these variables was greater in SHR than in WKY rats. In addition, an adenovirus vector encoding dominant-negative Rho-kinase decreased blood pressure, heart rate, and urinary norepinephrine excretion in both WKY rats and SHR in an awake and free-moving state. The magnitude of decreases in these variables was also greater in SHR than in WKY rats. Furthermore, membrane RhoA expression and Rho-kinase activity in the NTS were enhanced in SHR compared with WKY rats. These observations indicate that the Rho/Rho-kinase pathway in the NTS contributes to blood pressure regulation via the sympathetic nervous system in vivo and suggest that activation of this pathway is involved in the central mechanisms of hypertension.     

RhoA/ROCK与糖尿病肾病

Rho具有与GTP及GDP结合的能力,同时具有GTP酶活性,通过与GTP、GDP结合形式的转换调控许多细胞内信号转导.糖尿病时在高糖环境下肾小球系膜细胞RhoA/Rho激酶活性增加,诱导激活蛋白(AP)-1、转化生长因子(TGF)-β、血管内皮生长因子(VEGF)等上调,抑制内皮型一氧化氮合酶(eNOS),增强Ca2+依赖的血管平滑肌收缩,在肾脏缺血、纤维化中起重要作用.他汀类药物亦通过抑制RhoA活性,对肾脏结构和功能起保护作用.     

Pressor response induced by central angiotensin II is mediated by activation of Rho/Rho-kinase pathway via AT1 receptors

OBJECTIVES: The brain renin-angiotensin system plays an important role in cardiovascular regulation and the pathogenesis of hypertension. Angiotensin II activates the Rho/Rho-kinase pathway in vascular smooth muscle cells and cardiomyocytes in vitro. The aim of the present study was to determine whether angiotensin II in the brainstem activates the Rho/Rho-kinase pathway, and, if so, whether this mechanism is involved in the central pressor action of angiotensin II. METHODS AND RESULTS: Angiotensin II infused intracisternally for 7 days in Wistar-Kyoto rats (WKY) increased systolic blood pressure (SBP) and urinary norepinephrine excretion. These responses were abolished by the co-infusion of Y-27632, a specific Rho-kinase inhibitor, or valsartan. The intracisternal infusion of Y-27632 or valsartan also reduced SBP and norepinephrine excretion in spontaneously hypertensive rats (SHR). Western blot analysis was performed to examine the expression levels of membranous RhoA and phosphorylated ezrin, radixin, and moesin (p-ERM), which reflects Rho/Rho-kinase activity. The expression levels of membranous RhoA and p-ERM in the brainstem were significantly greater in both angiotensin II-treated WKY and SHR than in vehicle-treated WKY. Valsartan reduced the expression levels of membranous RhoA and p-ERM in angiotensin II-treated WKY and SHR. Y-27632 reduced the expression levels of p-ERM in angiotensin II-treated WKY and SHR. CONCLUSIONS: These results suggest that the pressor response induced by intracisternally infused angiotensin II is substantially mediated by the activation of the Rho/Rho-kinase pathway via AT1 receptors of the brainstem in WKY, and that this pathway might be involved in the hypertensive mechanisms of SHR.     

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.     

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.