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

项目总结 越来越多的证据表明，暴露在空气污染物和环境颗粒物(PM)中会增加 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疾病 炎症状态和缺血性心脏病和中风的主要原因，这与 约占西方国家所有死亡人数的50%。最近的研究表明，与地壳相比 PM的来源，城市地区车辆特有的PM，与亚临床联系更强 动脉硬化。以交通为基础的化石燃料燃烧产生的PM可能含有大量的 多环芳烃(PAHs)，研究表明可以激活胞内的芳香烃 受体(AhR)并参与PM介导的动脉粥样硬化形成。最近的研究，包括我们自己的，暗示了 车辆特异性PM与AhR的相互作用是导致促炎水平升高的关键事件 细胞因子和泡沫细胞和动脉粥样硬化斑块的更大形成。高脂肪饮食的成分，如 当饱和脂肪酸和胆固醇水平升高时，会触发节点样受体蛋白的激活 (NLRP)3/血管组织中的炎症体。我们的工作表明AhR-R的病理生理之间存在联系。 和NLRP3/炎症小体介导的PM的交通相关空气污染(TRAP)和高 脂肪饮食(HFD)有助于激活免疫细胞和产生促炎因子，这些因子是 严重参与动脉粥样硬化的形成。中心假说是同时激活和相互作用 AHR和NLRP3/炎症体暴露结合高脂饮食可增强血管 主动脉壁的炎症和功能障碍，最终会增加动脉粥样硬化。我们相信， TRAP介导的巨噬细胞和树突状细胞AhR的激活，以及由AFP产生的血脂 高脂饮食，协同激活NLRP3/炎症小体，诱导促炎标志物基因和 动脉硬化。这一概念将在C57BL/6wt、APOE-/-、APOE-/-/AhR-/-和APOE-/-/NLRP3-/-小鼠身上进行测试。至 确定TRAP介导的动脉粥样硬化的机制，我们将研究AhR和NLRP3的作用 树突状细胞和巨噬细胞激活过程中的受体。此外，捕集器的化学成分将 进行分析以确定那些引起细胞反应的因素，例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 通过暴露在空气中促进动脉粥样硬化的机制和关键因素 污染物。对AhR与NLRP3/炎症体相互作用的新见解对 了解TRAP如何增加发生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.