Liang Bai1, Zhao Li1, Qianwei Li1, Hua Guan1, Sihai Zhao1, Ruihan Liu1, Rong Wang1, Jin Zhang1, Yuzhi Jia1, Jianglin Fan1, Nanping Wang1, Janardan K Reddy1, John Y-J Shyy2, Enqi Liu2. 1. From the Research Institute of Atherosclerotic Disease, Health Science Center and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China (L.B., Q.L., H.G., S.Z., R.L., R.W., E.L.), Laboratory Animal Center, Health Science Center (L.B., Q.L., H.G., S.Z., R.L., R.W., E.L.), Cardiovascular Research Center, School of Basic Medical Sciences, Health Science Center (L.B., Z.L., J.Z., N.W., J.Y.-J.S.), Xi'an Jiaotong University, Shaanxi, China; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL (Y.J., J.K.R.); Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan (J.F.); and Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (J.Y.-J.S.). 2. From the Research Institute of Atherosclerotic Disease, Health Science Center and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China (L.B., Q.L., H.G., S.Z., R.L., R.W., E.L.), Laboratory Animal Center, Health Science Center (L.B., Q.L., H.G., S.Z., R.L., R.W., E.L.), Cardiovascular Research Center, School of Basic Medical Sciences, Health Science Center (L.B., Z.L., J.Z., N.W., J.Y.-J.S.), Xi'an Jiaotong University, Shaanxi, China; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL (Y.J., J.K.R.); Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan (J.F.); and Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla (J.Y.-J.S.). liuenqi@mail.xjtu.edu.cn jshyy@ucsd.edu.
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.
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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