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  • Title: Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.
    Author: Bai L, Li Z, Li Q, Guan H, Zhao S, Liu R, Wang R, Zhang J, Jia Y, Fan J, Wang N, Reddy JK, Shyy JY, Liu E.
    Journal: Arterioscler Thromb Vasc Biol; 2017 Aug; 37(8):1470-1481. PubMed ID: 28642237.
    Abstract:
    OBJECTIVE: MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated. APPROACH AND RESULTS: To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1ΔMac/ApoE-/-) mice and found that atherosclerosis was greater in MED1ΔMac/ApoE-/- mice than in MED1fl/fl/ApoE-/- littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1ΔMac/ApoE-/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1ΔMac mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPARγ (peroxisome proliferator-activated receptor γ) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPARγ and MED1 increased the binding of PPARγ or MED1 to the PPAR response elements of M2 marker genes. CONCLUSIONS: Our data suggest that MED1 is required for the PPARγ-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPARγ-regulated transactivation.
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