Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice

Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1260-7. doi: 10.1161/ATVBAHA.110.220202. Epub 2011 Mar 24.

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.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / physiology*
  • Atherosclerosis / etiology*
  • Cholesterol / metabolism
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Humans
  • Interleukin-8 / physiology
  • Lipoproteins, LDL / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nicotiana / toxicity
  • Polychlorinated Dibenzodioxins / toxicity
  • RNA, Messenger / analysis
  • Receptors, Aryl Hydrocarbon / physiology*
  • Receptors, Interleukin-8B / physiology*
  • U937 Cells
  • Vascular Endothelial Growth Factor A / genetics
  • Vasculitis / etiology*

Substances

  • Apolipoproteins E
  • Interleukin-8
  • Lipoproteins, LDL
  • Polychlorinated Dibenzodioxins
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Receptors, Interleukin-8B
  • Vascular Endothelial Growth Factor A
  • Cholesterol
  • Cytochrome P-450 CYP1A1