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: 10185061
• 负责人: Cyndya Adriana Shibao
• 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/10185061
• 关键词: 3-nitrotyrosine; Acetylcholine; Acetylcholinesterase Inhibitors; African American; 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; Hispanics; 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.

项目概要 内皮功能障碍是一种促血栓形成、炎症性疾病，会导致血管反应性受损。 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，非裔美国人 (AA) 的内皮功能受损。 非裔美国人的心血管发病率和死亡率也比非裔美国人高出 20% 白人或西班牙裔。内皮功能障碍是由活性氧过度产生引起的 （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；我们之前的工作发现NADPH氧化酶的激活 通过形成高度免疫原性的异黄兰素（IsoLG-蛋白）促进血管氧化 加合物）在外周单核细胞（PBMC）中，刺激抗原呈递细胞（APC）和 炎症介质。炎症和氧化应激由副交感神经调节 系统（PNS）。我们和其他人发现，与白人相比，AA 降低了三七总皂甙活性。我们的 肥胖 AA 女性的初步数据发现，刺激 PNS 胆碱能传递 乙酰胆碱酯酶抑制剂加兰他敏可阻止氧化应激和炎症的产生 由脂质诱导的细胞因子。当前提案的总体目标是确定是否需要长期治疗 加兰他敏可改善 AA 中的内皮功能障碍和血管氧化应激。为此，我们将 进行概念验证、盲法、随机、安慰剂对照研究，以测试 3 个月的效果 加兰他敏（16 毫克/天）治疗血管氧化应激和 AA 中受损的血管反应性。 具体来说，我们将评估加兰他敏治疗是否抑制 NADPH-IsoLG 形成的激活 以及随后 PBMC 中的免疫原性反应。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 同一研究对象的血管反应性。计划的研究将提供全面的评估 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 AA 的内皮功能障碍，这是一个具有高 CVD风险，我们将发现一种新的机制，可以改变氧化和免疫原性反应 这一人群将为开发更有效的治疗方法提供潜在途径 减少CVD。