Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

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 Delta Mac/ApoE(-/-)) mice and found that atherosclerosis was greater in MED1(Delta Mac)/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(Delta Mac)/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(Delta Mac) mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPAR gamma (peroxisome proliferator-activated receptor gamma) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPAR. and MED1 increased the binding of PPAR gamma or MED1 to the PPAR response elements of M2 marker genes. Conclusions-Our data suggest that MED1 is required for the PPAR.-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPAR gamma-regulated transactivation.