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.

项目摘要 内皮功能障碍，一种促脉症，炎症状况，导致血管反应受损受损 动脉粥样硬化和心血管疾病（CVD）发展的早期可逆步骤。多个研究 一贯表明，与白人相比，非洲裔美国人（AAS）的内皮功能受损。 非洲裔美国人的CV发病率和死亡率比 白人或西班牙裔。内皮功能障碍是由活性氧的生产过多引起的 （ROS），特别是超氧化物，会干扰内皮衍生的一氧化氮信号通路。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 通过形成高度免疫原性异甲素（Isalg-protein）来促进血管氧化 加合物）在周围单核细胞（PBMC）中，刺激抗原呈递细胞（APC）和 炎症介体。副交感神经来调节炎症和氧化应激 系统（PNS）。我们和其他人发现，与白人相比，AAS的PNS活性降低了。我们的 肥胖AA女性的初步数据发现，PNS胆碱能传播的刺激 乙酰胆碱酯酶抑制剂甘兰胺阻止了氧化应激和炎症的产生 脂质诱导的细胞因子。当前建议的总体目标是确定是否长期治疗 甘氨酸改善了AAS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，盲目，随机，安慰剂对照研究，以测试3个月的效果 甘氨酸（16 mg/day）治疗血管氧化应激和AAS血管反应受损。 具体而言，我们将评估Gaganamine治疗是否抑制了NADPH-ISOLG形成的激活 以及随后在PBMC中的免疫原性反应。此外，我们将确定甘兰敏是否 减少收获的内皮细胞（EC）中氧化应激和炎症的标志物，并改善 同一研究对象中的血管反应性。计划的研究将提供全面的评估 PNS胆碱能传播对内皮功能障碍的影响的基础机制。 如果我们的假设是正确的，而甘坦胺则改善了AAS的内皮功能障碍，那么 CVD的风险，我们将发现一种新的机制，可以改变氧化和免疫原性反应 这个人口，并将为开发针对更有效疗法的潜在途径 减少CVD。