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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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/Apo E-/-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.

Original languageEnglish (US)
Pages (from-to)1470-1481
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number8
DOIs
StatePublished - Aug 1 2017

Keywords

  • apolipoproteins
  • atherosclerosis
  • interleukins
  • macrophages
  • transcription factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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