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

项目摘要 越来越多的证据表明，暴露于空气污染物和环境颗粒物（PM）会提高 动脉粥样硬化性心血管疾病（ASCVD）的急性死亡风险。动脉粥样硬化是一种慢性 炎症性疾病和缺血性心脏病和中风的主要原因，这是与 大约占西方国家死亡人数的50%。最近的研究表明， PM的来源，城市地区的车辆特定PM，与亚临床 动脉粥样硬化基于交通的化石燃料燃烧产生的PM可能含有大量的 多环芳烃（PAHs），研究表明可以激活细胞溶质芳烃 受体（AhR），并有助于PM介导的动脉粥样硬化形成。最近的研究，包括我们自己的研究， 媒介物特异性PM与AhR的相互作用是导致促炎水平升高的关键事件 细胞因子和更多的泡沫细胞和动脉粥样硬化斑块的形成。高脂肪饮食的成分，如 饱和脂肪酸和胆固醇水平升高，触发Nod样受体蛋白的激活， （NLRP）3/血管组织中的炎性小体。我们的工作表明AhR的病理生理学之间的联系- 和NLRP 3/炎性体介导的途径，作为交通相关空气污染（TRAP）的PM和高浓度的 脂肪饮食（HFD）有助于激活免疫细胞和产生促炎因子， 与动脉粥样硬化形成密切相关。中心假设是，同时激活和相互作用， 来自TRAP暴露的AhR和NLRP 3/炎性小体与高脂饮食结合增强血管生成 主动脉壁的炎症和功能障碍，最终增加动脉粥样硬化。我们认为 TRAP介导的巨噬细胞和树突状细胞中AhR的活化，沿着血脂的产生， 高脂饮食，协同激活NLRP 3/炎性体以诱导促炎标记基因， 动脉粥样硬化将在C57 BL/6 wt、Apoe-/-、Apoe-/-/AhR-/-和Apoe-/-/NLRP 3-/-小鼠中测试该概念。到 为了确定TRAP介导的动脉粥样硬化的机制，我们将研究AhR和NLRP 3的作用， 受体在树突状细胞和巨噬细胞活化过程中。此外，TRAP的化学成分将 进行分析，以确定那些引起细胞反应，如诱导巨噬细胞和树突状细胞， 细胞特异性标记基因，它们是动脉粥样硬化的关键介质。这项研究旨在确定 通过暴露于空气中促进动脉粥样硬化的机制和关键参与者 污染物对AhR与NLRP 3/炎性小体相互作用的新认识对于 了解TRAP如何增加动脉粥样硬化的风险。

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.