Abstract 457: Transcription Coactivator MED1 Protects Against Atherosclerosis by Modulation of Macrophage Polarization

Abstract

Mediator 1 (MED1), a key subunit of the Mediator complex, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. It is well-known that MED1 play important roles in lipid metabolism. However, the role and underlying mechanisms of MED1 in atherosclerosis remains unclear. Here, macrophage-specific MED1 knockout (MED1 ΔMac ) mice were generated to investigate the contribution of MED1 on atherogenesis in vivo. We demonstrate that among mice deficient in apolipoprotein E (Apoe), the additional loss of macrophage MED1 (MED1 ΔMac /ApoE -/- ) exhibited significantly larger atherosclerotic lesions in the whole aortic tree and aortic root compared with MED1 fl/fl /ApoE -/- littermates on either the chow or the western diet, and these effects were also found in low-density lipoprotein (LDL) receptor-deficient (LDLR -/- ) mice reconstituted with bone marrow from MED1 ΔMac mice. Peritoneal macrophages from MED1 ΔMac /ApoE -/- mice had significantly increased expression of gene markers for M1-like macrophages, including IL-1β, IL6,COX2, iNOS, Gro1, MCP1 and TNFα, etc, whereas decreased levels of anti-inflammatory genes for M2-like macrophages, such as Arg1, Mrc1, Retnla, Chi3l3 and PPARγ. Over-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1 fl/fl /ApoE -/- macophages repressed the proinflammatory gene expression. Re-expression of MED1 using Ad/MED1 counteracted the high level of inflammatory gene in MED1 ΔMac /ApoE -/- macophages. Furthermore, gene expression profiling and PCR array showed that MED1-deficient macrophages exhibited the increased M1 targets and decreased M2 targets. These data demonstrate that MED1 expression by macrophages has anti-atherogenic effects via regulation of macrophage polarization. MED1 may be considered as a potential therapeutic target to treat atherosclerosis.