Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction

增强副交感神经活性，减少血管氧化应激和内皮功能障碍

• 批准号: 10418658
• 负责人: Annet Kirabo
• 金额: $ 75.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418658
• 关键词: 3-nitrotyrosine; Acetylcholine; Acetylcholinesterase Inhibitors; African American population; Antigen-Presenting Cells; Arteries; Atherosclerosis; Blinded; Blood Vessels; Caliber; Cardiovascular Diseases; Cells; Clinical; Data; Development; Dose; Endothelial Cells; Endothelium; Event; F2-Isoprostanes; Fatty acid glycerol esters; Functional disorder; Galantamine; Goals; Harvest; Hispanic Populations; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Infusion procedures; Intercellular adhesion molecule 1; Ischemia; Lipids; Measures; Mediating; Mononuclear; Morbidity - disease rate; Mus; NADP; NADPH Oxidase; Nerve; Nitric Oxide; Nitric Oxide Signaling Pathway; Obesity; Oxidative Stress; Parasympathetic Nervous System; Participant; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Placebos; Population; Production; Proteins; Reactive Oxygen Species; Signal Pathway; Skeletal Muscle; Source; Study Subject; Superoxides; Testing; Ultrasonography; Vasodilator Agents; Woman; Work; adduct; brachial artery; cardiovascular disorder risk; cholinergic; contrast enhanced; cytokine; effective therapy; endothelial dysfunction; experience; high risk; immune activation; immunogenic; improved; inflammatory marker; monocyte; mortality; novel; oxidation; randomized placebo controlled study; response; thrombotic; transmission process; vascular bed; vascular endothelial dysfunction; vascular inflammation

Project Summary Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies consistently shown that African Americans (AAs) have impaired endothelial function compared to whites. African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species (ROS), particularly superoxide which interferes with endothelial-derived nitric oxide signaling pathways. One of the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase contributes to vascular oxidation through the formation of highly immunogenic isolevuglandins (IsoLG-protein adducts) in peripheral mononuclear cells (PBMCs), which stimulates antigen presenting cells (APC) and inflammatory mediators. Inflammation and oxidative stress are modulated by the parasympathetic nervous system (PNS). We and others found that AAs have reduced PNS activity compared with whites. Our preliminary data in obese AA women found that stimulation of the PNS cholinergic transmission with the acetylcholinesterase inhibitor, galantamine, blocked the production of oxidative stress and inflammatory cytokines induced by lipids. The overall goal of the current proposal is to determine if prolonged treatment with galantamine improves endothelial dysfunction and vascular oxidative stress in AAs. For this purpose, we will conduct a proof-of-concept, blinded, randomized, placebo-controlled study to test the effect of 3-month treatment with galantamine (16 mg/day) on vascular oxidative stress and impaired vascular reactivity in AAs. Specifically, we will evaluate whether galantamine treatment inhibits the activation of NADPH-IsoLG formation and the subsequent immunogenic responses in PBMCs. Furthermore, we will determine if galantamine decreases markers of oxidative stress and inflammation in harvested endothelial cells (ECs) and improves vascular reactivity in the same study subjects. The planned studies will provide a comprehensive assessment of the mechanism underlying the effect of increased PNS cholinergic transmission on endothelial dysfunction. If our hypothesis is correct, and galantamine improves endothelial dysfunction in AAs, a population with a high risk for CVD, we will discover a novel mechanism that could alter the oxidative and immunogenic responses in this population and will offer a potential pathway for the development of more effective therapies aimed at decreasing CVD.

项目摘要 内皮功能障碍是一种导致血管反应性受损的促血栓形成的炎症性疾病， 动脉粥样硬化和心血管疾病（CVD）发展的早期可逆步骤。多项研究 一致表明，与白人相比，非洲裔美国人（AAs）的内皮功能受损。 非裔美国人的CV发病率也不成比例地高于非裔美国人， 白人或西班牙裔内皮功能障碍是由活性氧的过度产生引起的 (ROS)特别是干扰内皮源性一氧化氮信号通路的超氧化物。之一 超氧化物的主要来源是NADPH氧化酶，我们以前的工作发现NADPH氧化酶的激活 通过形成高免疫原性的异evuglandin（IsoLG-蛋白）促进血管氧化 加合物），其刺激抗原呈递细胞（APC）和 炎症介质。炎症和氧化应激受副交感神经调节 系统（PNS）。我们和其他人发现，与白人相比，AA降低了PNS活性。我们 肥胖AA妇女的初步数据发现， 乙酰胆碱酯酶抑制剂加兰他敏阻断了氧化应激和炎症反应的产生。 脂质诱导的细胞因子。目前提案的总体目标是确定是否延长治疗， 加兰他敏改善AA中的内皮功能障碍和血管氧化应激。为此，我们将 进行一项概念验证、设盲、随机、安慰剂对照研究，以测试3个月的效果 用加兰他敏（16 mg/天）治疗对AA中血管氧化应激和受损血管反应性的影响。 具体而言，我们将评估加兰他敏治疗是否抑制NADPH-IsoLG形成的活化 以及随后在PBMC中的免疫原性应答。此外，我们将确定加兰他敏是否 减少收获的内皮细胞（EC）中的氧化应激和炎症标志物，并改善 在相同的研究对象中的血管反应性。计划中的研究将提供一个全面的评估 PNS胆碱能传递增加对内皮功能障碍影响的机制。 如果我们的假设是正确的，加兰他敏可以改善动脉粥样硬化患者的内皮功能障碍， 我们将发现一种新的机制，可以改变氧化和免疫原性反应， 这一人群，并将提供一个潜在的途径，为发展更有效的治疗，旨在 降低CVD。