Enhancing parasympathetic activity to reduce vascular oxidative stress and endothelial dysfunction

项目摘要 内皮功能障碍是一种促血栓形成的炎症状态，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 一贯表明，与白人相比，非裔美国人(AA)的内皮功能受损。 非洲裔美国人的心血管发病率和死亡率也比美国人高出20% 白人或西班牙裔。血管内皮细胞功能障碍是由活性氧产生过多引起的 (ROS)，特别是干扰内皮源性一氧化氮信号通路的超氧化物歧化酶。其中之一 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IsoVuglandins(IsoLG-蛋白)促进血管氧化 外周单个核细胞(PBMC)中的加合物)，刺激抗原提呈细胞(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，AAS降低了PNS的活性。我们的 在肥胖的再障女性中的初步数据发现，刺激三叉神经节胆碱能传递 乙酰胆碱酯酶抑制剂，加兰他明，阻止氧化应激和炎症的产生 脂类诱导的细胞因子。目前提案的总体目标是确定延长治疗时间是否会导致 加兰他明改善腹主动脉内皮细胞功能障碍和血管氧化应激。为此，我们将 进行一项概念验证、随机、安慰剂对照研究，以测试为期3个月的 加兰他敏(16 mg/d)治疗对腹主动脉粥样硬化患者血管氧化应激和血管反应性受损的影响。 具体地说，我们将评估加兰他明治疗是否抑制NADPH-IsoLG形成的激活 以及随后的PBMC的免疫原性反应。此外，我们将确定加兰他明是否 减少收获内皮细胞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。计划中的研究将提供一个全面的评估 三七总皂苷胆碱能传递增加对内皮细胞功能障碍影响的机制。 如果我们的假设是正确的，加兰他明改善了AAS的内皮功能障碍，这是一个高 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在 并将为开发更有效的治疗方法提供一条潜在的途径 降低脑血管密度。

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.