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 language | English (US) |
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Pages (from-to) | 1470-1481 |
Number of pages | 12 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 37 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2017 |
Keywords
- apolipoproteins
- atherosclerosis
- interleukins
- macrophages
- transcription factors
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine