title: Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice.
abstract: OBJECTIVE
  Exposure to dioxins has been shown to contribute to the development of inflammatory diseases, such as atherosclerosis. Macrophage-mediated inflammation is a critical event in the initiation of atherosclerosis. Previously, we showed that treatment of macrophages with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to aryl hydrocarbon receptor (AhR)-dependent activation of inflammatory mediators and the formation of cholesterol-laden foam cells. However, the mechanisms responsible for the formation of atherosclerotic lesions mediated through AhR have not been identified.
  
  
  RESULTS
  An in vitro macrophage and an apolipoprotein E (ApoE)-/- mouse model were used to determine whether chemokines and their receptors are responsible for the AhR-mediated atherogenesis. Exposure of ApoE-/- mice to TCDD caused a time-dependent progression of atherosclerosis, which was associated with induction of inflammatory genes, including interleukin-8, as well as F4/80 and matrix metalloproteinase-12. A high-fat diet enhanced the TCDD-mediated inflammatory response and aggravated the formation of complex atheromas. Treatment with a CXCR2 inhibitor and an AhR antagonist reduced the TCDD-induced progression of early atherosclerotic lesions in ApoE-/- mice.
  
  
  CONCLUSIONS
  The results suggest that CXCR2 mediates the atherogenic activity of environmental pollutants, such as dioxins, and contributes to the development of atherosclerosis through the induction of a vascular inflammatory response by activating the AhR-signaling pathway.
authors: Department of Environmental Toxicology, University of California, Davis, CA 95616, USA.
authors: Dalei
authors: D
authors: Wu
authors: Noriko
authors: N
authors: Nishimura
authors: Victoria
authors: V
authors: Kuo
authors: Oliver
authors: O
authors: Fiehn
authors: Sevini
authors: S
authors: Shahbaz
authors: Laura
authors: L
authors: Van Winkle
authors: Fumio
authors: F
authors: Matsumura
authors: Christoph Franz Adam
authors: CF
authors: Vogel
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D012333:RNA, Messenger / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D014026:Nicotiana / Q000633:toxicity; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014657:Vasculitis / Q000209:etiology*
chemical_list: D001057:Apolipoproteins E; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D023063:Receptors, Interleukin-8B; D042461:Vascular Endothelial Growth Factor A; D002784:Cholesterol; D019363:Cytochrome P-450 CYP1A1