Air pollution, atherosclerosis, and the role of the aryl hydrocarbon receptor

空气污染、动脉粥样硬化和芳烃受体的作用

• 批准号: 10540334
• 负责人: CHRISTOPH F A VOGEL
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540334
• 关键词: Acute; Air Pollutants; Air Pollution; Aorta; Apolipoprotein E; Aromatic Polycyclic Hydrocarbons; Arterial Fatty Streak; Aryl Hydrocarbon Receptor; Atherosclerosis; Biological Markers; Biological Response Modifiers; Blood Vessels; CASP1 gene; Cardiovascular Diseases; Cells; Cessation of life; Chemicals; Cholesterol; Chronic; Country; Data; Dendritic Cells; Dendritic cell activation; Development; Effectiveness; Environmental Pollutants; Event; Exposure to; Fatty Acids; Female; Foam Cells; Fossil Fuels; Functional disorder; Genes; Genetic; Health; High Fat Diet; High Prevalence; Immune; Immune system; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-1 beta; Knock-out; Lead; Link; Lipids; Macrophage; Macrophage Activation; Mediating; Mediator; Molecular; Mus; Myocardial Ischemia; Obesity; Particulate Matter; Pathway interactions; Population; Predisposition; Prevention; Production; Promoter Regions; Receptor Signaling; Reporting; Risk; Role; Sampling; Saturated Fatty Acids; Site; Source; Stroke; System; Testing; Tissues; Transcriptional Activation; Vascular Diseases; Work; atherogenesis; blood lipid; chromatin immunoprecipitation; cytokine; design; dietary control; experimental study; immune activation; inflammatory marker; insight; male; mortality risk; mouse model; novel; oxidized low density lipoprotein; receptor; recruit; response; synergism; therapy development; traffic-related air pollution; transcription factor; urban area; vascular inflammation

PROJECT SUMMARY There is increasing evidence that exposure to air pollutants and ambient particulate matter (PM) elevates the acute risk of mortality from atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is a chronic inflammatory condition and the primary cause of ischemic heart disease and stroke, which are associated with approximately 50% of all deaths in Western countries. Recent studies indicate that compared to crustal sources of PM, vehicular-specific PM in urban areas, is more strongly associated with subclinical atherosclerosis. PM generated by traffic-based fossil fuel combustion can contain significant amounts of polycyclic aromatic hydrocarbons (PAHs), which studies show can activate the cytosolic aryl hydrocarbon receptor (AhR) and contribute to PM-mediated atherogenesis. Recent work, including our own, implicates the interaction of vehicular-specific PM with AhR as a key event leading to elevated levels of pro-inflammatory cytokines and greater formation of foam cells and atherosclerotic plaques. Components of a high-fat diet, such as elevated levels of saturated fatty acids and cholesterol, trigger activation of Nod-like receptor proteins (NLRP)3/inflammasome in vascular tissue. Our work indicates linkages between the pathophysiology of AhR- and NLRP3/inflammasome-mediated pathways as both PM from traffic-related air pollution (TRAP) and a high- fat diet (HFD) contribute to the activation of immune cells and production of pro-inflammatory factors, which are critically involved in atherogenesis. The central hypothesis is that the simultaneous activation and interaction of AhR and NLRP3/inflammasome from TRAP exposure combined with a high-fat diet enhances vascular inflammation and dysfunction in the aortic wall, which ultimately increases atherosclerosis. We believe that the TRAP-mediated activation of AhR in macrophages and dendritic cells, along with blood lipids generated from a high-fat diet, synergistically activate the NLRP3/inflammasome to induce pro-inflammatory marker genes and atherosclerosis. This concept will be tested in C57BL/6 wt, Apoe-/-, Apoe-/-/AhR-/-, and Apoe-/-/NLRP3-/- mice. To identify the mechanisms of TRAP-mediated atherosclerosis, we will examine the role of the AhR and NLRP3 receptor during activation of dendritic cells and macrophages. In addition, chemical components of TRAP will be analyzed to identify those that cause cellular responses, such as induction of macrophage- and dendritic cell-specific marker genes, which are critical mediators of atherosclerosis. The study is designed to identify the mechanisms and key players that are responsible for promoting atherosclerosis through exposure to air pollutants. New insight into the interacting role of the AhR with the NLRP3/inflammasome is critical to understand how TRAP increases the risk of developing atherosclerosis.

项目摘要 有越来越多的证据表明，暴露于空气污染物和环境颗粒物（PM）提高了 动脉粥样硬化心血管疾病（ASCVD）死亡的急性风险。动脉粥样硬化是一种慢性 炎症状况以及缺血性心脏病和中风的主要原因，与 西方国家的所有死亡人数中约有50％。最近的研究表明，与地壳相比 PM的来源是城市地区的车辆特异性PM，与亚临床更密切相关 动脉粥样硬化。基于流量的化石燃料燃烧产生的PM可能包含大量 多环芳烃（PAHS），研究表明可以激活胞质芳基烃 受体（AHR）并有助于PM介导的动脉粥样硬化。最近的工作，包括我们自己的 车辆特异性PM与AHR的相互作用作为关键事件，导致促炎水平升高 细胞因子和泡沫细胞和动脉粥样硬化斑块的更大形成。高脂饮食的组成部分， 随着饱和脂肪酸和胆固醇水平升高，触发了点状受体蛋白的激活 （NLRP）3/血管组织中的炎性体。我们的工作表明AHR的病理生理学之间的联系 和NLRP3/炎性介导的途径是与交通相关的空气污染（陷阱）的PM和高 脂肪饮食（HFD）有助于免疫细胞的激活和促炎因子的产生，这是 严重参与动脉粥样硬化。中心假设是同时激活和相互作用 AHR和NLRP3/炎症体来自陷阱暴露与高脂饮食相结合增强血管 主动脉壁的炎症和功能障碍，最终增加了动脉粥样硬化。我们相信 陷阱介导的巨噬细胞和树突状细胞中AHR的激活以及由A 高脂饮食，协同激活NLRP3/炎症体，以诱导促炎性标记基因和 动脉粥样硬化。该概念将在C57BL/6 WT，APOE-/ - ，APOE-/ - /AHR - / - 和APOE-/ - / - /NLRP3 - / - 小鼠中进行测试。到 确定陷阱介导的动脉粥样硬化的机制，我们将检查AHR和NLRP3的作用 树突状细胞和巨噬细胞激活期间受体。此外，陷阱的化学成分将 进行分析以识别引起细胞反应的人，例如巨噬细胞和树突状的诱导 细胞特异性标记基因，它们是动脉粥样硬化的关键介体。该研究旨在确定 负责通过暴露的机制和主要参与者促进动脉粥样硬化 污染物。对AHR与NLRP3/炎症体的相互作用作用的新见解对于 了解陷阱如何增加发生动脉粥样硬化的风险。

项目成果

Chemical and Toxicological Properties of Emissions from a Light-Duty Compressed Natural Gas Vehicle Fueled with Renewable Natural Gas.

• DOI: 10.1021/acs.est.0c04962
• 发表时间: 2021-03-02
• 期刊: Environmental science & technology
• 影响因子: 11.4
• 作者: Li Y;Xue J;Peppers J;Kado NY;Vogel CFA;Alaimo CP;Green PG;Zhang R;Jenkins BM;Kim M;Young TM;Kleeman MJ
• 通讯作者: Kleeman MJ