Regulation of Rho Signaling by S-Nitrosothiols

S-亚硝基硫醇对 Rho 信号传导的调节

• 批准号: 7580056
• 负责人: A RICHARD WHORTON
• 金额: $ 31.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580056
• 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; Cells; Chronic Disease; Data; Development; Endothelial Cells; Endothelin; GTP-Binding Proteins; Genes; Goals; Hypertension; Hypertrophy; Hypoxia; Inbred SHR Rats; Inflammation; Lead; Lesion; Leukocytes; Lung; Mediating; Mediator of activation protein; Membrane; Modification; Molecular; 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; 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; myosin phosphatase; novel; pressure; prevent; public health relevance; rho; rhoA GTP-Binding Protein; vascular inflammation; vasoconstriction

DESCRIPTION (provided by applicant): 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 occurring in the circulation may be particularly 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 implication 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 vasculature 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 addition, 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. PUBLIC HEALTH RELEVANCE: The aim of this research is to understand mechanisms through which nitric oxide derivatives resist development of cardiovascular disease especially those related to vascular inflammation. Results from our studies will provide insight into prevention and development of potential therapeutic strategies.

描述（由申请人提供）：ras超家族的小GTP结合蛋白被认为在心血管疾病的发展中起关键作用。在这方面，Rho蛋白特别重要。例如，通过Rho激酶的RhoA信号传导调节多种血管功能，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。Rho通路被血管活性激动剂激活，包括血管紧张素II、内皮素I、凝血酶、血栓烷A2等，其过度活动通常与心血管疾病相关，并导致全身性和肺动脉高压、血管炎症和动脉粥样硬化。Rho通路激活可以在高血压发展的早期看到，Rho激酶抑制剂松弛血管组织，降低血压并抑制平滑肌增殖和血管重塑。与RhoA活化相反，一氧化氮（NO）的衍生物降低血压、抑制血栓形成、抑制平滑肌增殖并且通常起抗动脉粥样硬化作用。循环中的S-亚硝基硫醇可能对这些效应特别重要。RhoA通路和NO产生之间的相互作用最近已经出现，表明NO合成减少导致RhoA信号传导增加。虽然这种作用的机制尚不清楚，但我们最近发现，来源于NO的S-亚硝基硫醇氧化并可逆地抑制纯化的RhoA蛋白中的GDP-GTP交换，抑制RhoA向膜的易位并阻断Rho激酶下游靶标的修饰。这些发现的潜在含义是NO衍生物如S-亚硝基硫醇对抗依赖于RhoA/Rho激酶激活的机制。因此，我们的假设是S-亚硝基硫醇负调节Rho信号传导，保护血管免受促动脉粥样硬化机制的影响。我们将使用分子、细胞和动物模型来研究这一假设。从这些研究中收集的数据将具有重要的意义，并提出一氧化氮调节血管功能的新机制。此外，基于S-亚硝基硫醇的药理学方法是可行的，并可能导致新的治疗方法，其中可能包括高血压疾病的急性治疗和动脉粥样硬化相关并发症的慢性治疗。 公共卫生关系：本研究的目的是了解一氧化氮衍生物抵抗心血管疾病发展的机制，特别是与血管炎症相关的机制。我们的研究结果将为预防和开发潜在的治疗策略提供见解。