The serotonergic system in periaortic fat regulates regional aortopathy development

主动脉周围脂肪中的血清素能系统调节区域主动脉病的发展

基本信息

批准号：
10651042
负责人：
Lisa A Cassis
金额：
$ 59.52万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651042
关键词：
Abdomen Adipocytes Anatomy Aneurysm Angiotensin II Aorta Aortitis Area Brown Fat Calcium Catabolism Cations Cd68 Chest Complement Dangerousness Data Deamination Development Diffuse Disease Elements Environmental Risk Factor Enzymes Exposure to Fatty acid glycerol esters Functional disorder Genetic Human Hydrogen Peroxide In Vitro Inflammasome Inflammation Infusion procedures Ion Channel Gating Left Length Ligands Link Lipopolysaccharides Macrophage Mediating Mitochondria Modeling Monoamine Oxidase Mus Mutant Strains Mice Myelogenous Necrosis Induction Neurons Neurotransmitters Peripheral Production Protein Isoforms Reactive Oxygen Species Regulation Reporting Respiration Risk Role Rupture Serotonergic System Serotonin Sex Chromosomes Side Source Stimulus Thermogenesis Thoracic aorta Tropisetron Tryptophan Tryptophan 5-monooxygenase Tunica Adventitia Vascular Diseases abdominal aorta abdominal fat antagonist aortic arch differential expression in vivo male mitochondrial dysfunction nerve supply neural new therapeutic target novel receptor recruit regional difference sex therapeutic target uptake

项目摘要

Aortopathies are dangerous vascular diseases with no known therapy that can occur in different aortic regions depending on genetic and environmental factors. Periaortic fat surrounding different regions of the aorta is composed of different adipocyte and neuronal elements and has been reported to be associated with human aortopathies. Preliminary data demonstrate levels of serotonin (5HT) in periaortic fat differ according to aortic region, and similarly, there is differential expression of the 5HT3 receptor (Htr3) along the aortic length. Infusion of angiotensin II (AngII), a well-known stimulus of regional aortopathies, was associated with regulation of 5HT levels in thoracic brown periaortic, but not white abdominal periaortic fat, and AngII promoted neuronal release of 5HT from thoracic aortic sections with adherent periaortic fat. Moreover, J774 macrophages responded to 5HT to promote inflammation and altered basal mitochondrial respiration through an Htr3-mediated mechanism. Notably, administration of an Htr3 antagonist to AngII-infused mice abolished regional aortopathies. We hypothesize that periaortic fat-derived 5HT acts at Htr3 on resident or recruited macrophages within periaortic fat to promote aortic adventitial inflammation and stimulate mitochondrial reactive oxygen species production, contributing to AngII-induced aortopathies. An ability of periaortic fat- derived 5HT and macrophage Htr3 to influence the aortic adventitia is likely due to the absence of an anatomic barrier. Moreover, we hypothesize that regional differences in periaortic fat-derived production of 5HT, its regulation by AngII, and its ability to stimulate macrophage Htr3 contribute to regional differences in AngII- induced aortopathies. Aim 1 will define the impact of regional differences in the synthesis of 5HT and its regulation by AngII in periaortic fat on the regional development and progression of AngII-induced aortopathies. Aim 2 will define mechanisms of macrophage Htr3 on regional development of AngII-induced aortopathies and investigate mechanisms of 5HT/Htr3 to promote macrophage inflammation and mitochondrial dysfunction. Results from these studies will identify a novel role for periaortic fat, through a 5HT/Htr3 mechanism, on regional aortopathy development and may identify new therapeutic targets optimized to specific regional aortopathies.

主动脉病是危险的血管疾病，目前尚无已知的治疗方法，可发生在不同的主动脉区域取决于遗传和环境因素。主动脉不同区域周围的主动脉周围脂肪由不同的脂肪细胞和神经元元素组成，据报道与人类有关主动脉病。初步数据表明，主动脉周围脂肪中的血清素 (5HT) 水平因主动脉的不同而不同。类似地，5HT3 受体 (Htr3) 沿主动脉长度也存在差异表达。血管紧张素 II (AngII) 的输注是一种众所周知的局部主动脉病刺激物，与调节胸部棕色主动脉周围脂肪中的 5HT 水平，但不调节白色腹部主动脉周围脂肪，并且 AngII 促进神经元从附着有主动脉周围脂肪的胸主动脉切片中释放 5HT。此外，J774 巨噬细胞对 5HT 做出反应，通过以下方式促进炎症并改变基础线粒体呼吸： Htr3 介导的机制。值得注意的是，对注入 AngII 的小鼠施用 Htr3 拮抗剂的情况被废除区域性主动脉病。我们假设主动脉周围脂肪衍生的 5HT 作用于常驻或招募的 Htr3 主动脉周围脂肪内的巨噬细胞促进主动脉外膜炎症并刺激线粒体活性氧的产生，导致 AngII 诱发的主动脉病。主动脉周围脂肪的能力衍生的 5HT 和巨噬细胞 Htr3 影响主动脉外膜可能是由于缺乏解剖学结构障碍。此外，我们假设主动脉周围脂肪产生的 5HT 的区域差异，其 AngII 的调节及其刺激巨噬细胞 Htr3 的能力导致 AngII 的区域差异诱发主动脉病。目标 1 将定义区域差异对 5HT 及其合成的影响主动脉周围脂肪中AngII对AngII诱导的区域发育和进展的调节主动脉病。目标 2 将定义巨噬细胞 Htr3 对 AngII 诱导的区域发育的机制主动脉病并研究 5HT/Htr3 促进巨噬细胞炎症和线粒体的机制功能障碍。这些研究的结果将通过 5HT/Htr3 确定主动脉周围脂肪的新作用机制，关于区域主动脉病的发展，并可能确定优化的新治疗目标特定的区域主动脉病。