Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

Liang Bai; Zhao Li; Qianwei Li; Hua Guan; Sihai Zhao; Ruihan Liu; Rong Wang; Jin Zhang; Yuzhi Jia; Jianglin Fan; Nanping Wang; Janardan K Reddy; John Y-J Shyy; Enqi Liu

doi:10.1161/ATVBAHA.117.309672

Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1470-1481. doi: 10.1161/ATVBAHA.117.309672. Epub 2017 Jun 22.

Authors

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

Affiliations

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 (MED1^ΔMac/ApoE^-^/-) mice and found that atherosclerosis was greater in MED1^ΔMac/ApoE^-/- mice than in MED1^fl/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 MED1^ΔMac/ApoE^-/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1^ΔMac 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.

Keywords: apolipoproteins; atherosclerosis; interleukins; macrophages; transcription factors.

Publication types

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

MeSH terms

Acetylation
Animals
Aorta / immunology
Aorta / metabolism*
Aorta / pathology
Aortic Diseases / genetics
Aortic Diseases / metabolism
Aortic Diseases / pathology
Aortic Diseases / prevention & control*
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Atherosclerosis / genetics
Atherosclerosis / metabolism
Atherosclerosis / pathology
Atherosclerosis / prevention & control*
Binding Sites
Bone Marrow Transplantation
Cell Plasticity*
Disease Models, Animal
Epigenesis, Genetic
Gene Expression Regulation
Genetic Predisposition to Disease
Histones / metabolism
Immunity, Innate
Macrophages, Peritoneal / immunology
Macrophages, Peritoneal / metabolism*
Macrophages, Peritoneal / pathology
Macrophages, Peritoneal / transplantation
Male
Mediator Complex Subunit 1 / deficiency
Mediator Complex Subunit 1 / genetics
Mediator Complex Subunit 1 / metabolism*
Methylation
Mice
Mice, Knockout
PPAR gamma / metabolism
Phenotype
Plaque, Atherosclerotic
RAW 264.7 Cells
RNA Interference
Receptors, LDL / deficiency
Receptors, LDL / genetics
Response Elements
Signal Transduction
Transcription, Genetic
Transcriptional Activation
Transfection

Substances

Apolipoproteins E
Histones
Med1 protein, mouse
Mediator Complex Subunit 1
PPAR gamma
Receptors, LDL

Abstract

Publication types

MeSH terms

Substances

Grants and funding