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: 7748012
• 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/7748012
• 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发挥关键作用。在这方面，Rho蛋白尤为重要。例如，RhoA信号通过Rho-Kinase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，它们的过度激活通常与心血管疾病有关，并导致全身和肺高压、血管炎症和动脉粥样硬化。Rho通路的激活可见于高血压的早期发展，Rho-Kinase抑制剂松弛血管组织，降低血压，抑制血管的增殖和血管重塑。与RhoA的激活相反，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，通常起到抗动脉粥样硬化的作用。循环中的亚硝硫醇对这些影响可能特别重要。RhoA途径和NO产生之间的相互作用最近出现，有证据表明，NO合成减少会导致RhoA信号增加。虽然这种作用的机制尚不清楚，但我们最近发现，由NO产生的S-亚硝硫醇氧化并可逆地抑制纯化的RhoA蛋白中的GDPGTP交换，抑制RhoA向膜的转位，并阻断Rho-Kinase下游靶点的修饰。这些发现的潜在含义是，像S-亚硝硫醇这样的NO-衍生物反对依赖于RhoA/Rho-Kinase激活的机制。因此，我们的假设是，S-亚硝硫醇负性调节Rho信号，保护血管系统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说。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，其中可能包括急性治疗高血压疾病和慢性治疗与动脉粥样硬化相关的并发症。 公共卫生相关性：这项研究的目的是了解一氧化氮衍生物阻止心血管疾病发展的机制，特别是那些与血管炎症相关的疾病。我们的研究结果将为预防和开发潜在的治疗策略提供洞察力。