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

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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.