Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice.
Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice.
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DOI：
10.1161/atvbaha.110.220202
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Vogel CF
中科院分区：
文献类型：
--
作者：
Wu D;Nishimura N;Kuo V;Fiehn O;Shahbaz S;Van Winkle L;Matsumura F;Vogel CF
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. An in vitro macrophage and an 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 (IL)-8 as well as F4/80 and matrix metalloproteinase (MMP)-12. High fat diet enhanced the TCDD-mediated inflammatory response and deteriorated 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. 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.
