Regulation of Rho Signaling by S-Nitrosothiols

S-亚硝基硫醇对 Rho 信号传导的调节

基本信息

批准号：
8235748
负责人：
A RICHARD WHORTON
金额：
$ 30.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235748
关键词：
Acute Angiotensin II Animal Model Antiatherogenic Aorta Atherosclerosis Blood Circulation Blood Pressure Blood Vessels Cardiovascular Diseases Cell Adhesion Molecules Cell Communication Cell Differentiation process Cell Proliferation Cell model Cells Chronic Disease Data Development Endothelial Cells Endothelin GTP-Binding Proteins Genes Goals Guanosine Triphosphate Hypertension Hypertrophy Hypoxia Inbred SHR Rats Lead Lesion Leukocytes Lung Mediating Mediator of activation protein Membrane Modification Molecular Models Mus Muscle Contraction Nitric Oxide Nitric Oxide Pathway Nuclear Pathway interactions Patients Phosphorylation Play Prevention Production Proteins Pulmonary Hypertension Rattus Regulation Research Rho-associated kinase Role S-Nitrosothiols Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Therapeutic Thrombin Thromboplastin Thromboxane A2 Tissues Vascular remodeling Vasoconstrictor Agents Vasodilation base blood pressure regulation cell motility design in vivo inflammatory marker insight kinase inhibitor migration molecular modeling myosin phosphatase novel pressure prevent rho rhoA GTP-Binding Protein vascular inflammation vasoconstriction

项目摘要

Small GTP binding proteins of the ras superfamily are recognized to play a key role in development of cardiovascular disease. In this regard Rho proteins are particularly important. For example RhoA signaling through Rho-kinases regulate diverse vascular functions including smooth muscle contraction and migration, leukocyte-endothelial cell interactions, tissue factor expression, cell differentiation and cell proliferation. The Rho pathway is activated by vasoactive agonist including angiotensin II, endothelin I, thrombin, thromboxane A2, etc., whose over-activity is commonly associated with cardiovascular disease and contributes to systemic and pulmonary hypertension, vascular inflammation, and atherosclerosis. Rho pathway activation can be seen early in development of hypertension and Rho-kinase inhibitors relax vascular tissues, reduce blood pressure and inhibit smooth muscle proliferation and vascular remodeling. In contrast to RhoA activation, derivatives of nitric oxide (NO) reduce blood pressure, inhibit thrombogenesis, inhibit smooth muscle proliferation and generally play an anti- atherogenic role. S-nitrosothiols occuring in the circulation may be particulary important for these effects. Interactions between the RhoA pathway and NO production have recently emerged with the demonstration that decreased NO synthesis leads to increased RhoA signaling. While the mechanisms for this effect is not known, we have recently found that S-nitrosothiols derived from NO, oxidize and reversibly inhibit GDP- GTP exchange in purified RhoA protein, inhibit translocation of RhoA to the membrane and block modification of downstream targets of Rho-kinase. The potential implications of these findings is that NO-derivatives such as S-nitrosothiols oppose mechanisms dependent on RhoA/Rho-kinase activation. Thus our hypothesis is that S-nitrosothiols negatively regulate Rho signaling protecting the vascularture from pro-atherogenic mechanisms. We will investigate this hypothesis using molecular, cellular and animal models. Data gathered from these studies will have important implications and suggest new mechanisms through which nitric oxide regulates vascular function. In addtion, pharmacologic approaches based on S-nitrosothiols are feasible and may lead to new therapies which may include acute treatment of hypertensive disorders and chronic treatment of complications associated with atherosclerosis.

ras 超家族的小 GTP 结合蛋白被认为在心血管疾病的发展。在这方面，Rho 蛋白尤其重要重要的。例如，RhoA 信号通过 Rho 激酶调节多种血管功能包括平滑肌收缩和迁移、白细胞-内皮细胞相互作用、组织因子表达、细胞分化和细胞增殖。罗河该途径由血管活性激动剂激活，包括血管紧张素 II、内皮素 I、凝血酶、血栓素A2等，其过度活性通常与心血管疾病并导致全身性高血压和肺动脉高压，血管炎症、动脉粥样硬化。 Rho 通路激活可以在早期发现高血压和 Rho 激酶抑制剂的发展可以放松血管组织，减少血压并抑制平滑肌增殖和血管重塑。在与 RhoA 激活相反，一氧化氮 (NO) 衍生物可降低血压，抑制血栓形成，抑制平滑肌增殖，一般起到抗血栓作用致动脉粥样硬化作用。循环中出现的 S-亚硝基硫醇可能特别重要为了这些效果。 RhoA 途径和 NO 产生之间的相互作用最近出现的证据表明，NO 合成减少会导致 RhoA 信号传导增强。虽然这种效应的机制尚不清楚，但我们已经最近发现，源自NO的S-亚硝基硫醇可以氧化并可逆地抑制GDP- 纯化的 RhoA 蛋白中的 GTP 交换，抑制 RhoA 向膜的易位以及 Rho 激酶下游靶点的阻断修饰。潜在影响这些发现的其中之一是 NO 衍生物，例如 S-亚硝基硫醇，会对抗机制依赖于 RhoA/Rho 激酶激活。因此我们的假设是 S-亚硝基硫醇负向调节 Rho 信号传导，保护血管免受促动脉粥样硬化的影响机制。我们将利用分子、细胞和动物来研究这个假设模型。从这些研究中收集的数据将产生重要影响并表明一氧化氮调节血管功能的新机制。另外，基于 S-亚硝基硫醇的药理学方法是可行的，并且可能会产生新的治疗可能包括高血压疾病的急性治疗和慢性疾病的治疗治疗与动脉粥样硬化相关的并发症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reductive ligation mediated one-step disulfide formation of S-nitrosothiols.

DOI：
10.1021/ol101863s
发表时间：
2010-09-17
期刊：
ORGANIC LETTERS
影响因子：
5.2
作者：
Zhang, Jiming;Li, Sheng;Zhang, Dehui;Wang, Hua;Whorton, A. Richard;Xian, Ming
通讯作者：
Xian, Ming

Reaction based fluorescent probes for hydrogen sulfide.

DOI：
10.1021/ol3008183
发表时间：
2012-04-20
期刊：
Organic letters
影响因子：
5.2
作者：
Liu C;Peng B;Li S;Park CM;Whorton AR;Xian M
通讯作者：
Xian M

Direct methods for detection of protein S-nitrosylation.

DOI：
10.1016/j.ymeth.2013.04.018
发表时间：
2013-08-01
期刊：
METHODS
影响因子：
4.8
作者：
Devarie-Baez, Nelmi O.;Zhang, Dehui;Li, Sheng;Whorton, A. Richard;Xian, Ming
通讯作者：
Xian, Ming