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

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 journal › Article › peer-review

27 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 language	English (US)
Pages (from-to)	1470-1481
Number of pages	12
Journal	Arteriosclerosis, thrombosis, and vascular biology
Volume	37
Issue number	8
DOIs	https://doi.org/10.1161/ATVBAHA.117.309672
State	Published - Aug 1 2017

Keywords

apolipoproteins
atherosclerosis
interleukins
macrophages
transcription factors

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/ATVBAHA.117.309672

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@article{7afb8f9f443a4c6f96b4bd03f99d9450,

title = "Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization",

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.",

keywords = "apolipoproteins, atherosclerosis, interleukins, macrophages, transcription factors",

author = "Liang Bai and Zhao Li and Qianwei Li and Hua Guan and Sihai Zhao and Ruihan Liu and Rong Wang and Jin Zhang and Yuzhi Jia and Jianglin Fan and Nanping Wang and Reddy, {Janardan K.} and Shyy, {John Y.J.} and Enqi Liu",

note = "Funding Information: This study was supported by grants from the National Natural Science Foundation of China (81200207, 81070250, 81670452, and 81270349 to L. Bai, E. Liu, J.Y.-J. Shyy), Natural Science Foundation of Shaanxi Province (2014JQ4138 to L. Bai), a Public Service Platform Grant from Shaanxi Province (2014FWPT-07 to E. Liu), and US National Institutes of Health grant HL108735 (J.Y.-J. Shyy). Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = aug,

day = "1",

doi = "10.1161/ATVBAHA.117.309672",

language = "English (US)",

volume = "37",

pages = "1470--1481",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins",

number = "8",

}

TY - JOUR

T1 - Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

AU - Bai, Liang

AU - Li, Zhao

AU - Li, Qianwei

AU - Guan, Hua

AU - Zhao, Sihai

AU - Liu, Ruihan

AU - Wang, Rong

AU - Zhang, Jin

AU - Jia, Yuzhi

AU - Fan, Jianglin

AU - Wang, Nanping

AU - Reddy, Janardan K.

AU - Shyy, John Y.J.

AU - Liu, Enqi

N1 - Funding Information: This study was supported by grants from the National Natural Science Foundation of China (81200207, 81070250, 81670452, and 81270349 to L. Bai, E. Liu, J.Y.-J. Shyy), Natural Science Foundation of Shaanxi Province (2014JQ4138 to L. Bai), a Public Service Platform Grant from Shaanxi Province (2014FWPT-07 to E. Liu), and US National Institutes of Health grant HL108735 (J.Y.-J. Shyy). Publisher Copyright: © 2017 American Heart Association, Inc.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - apolipoproteins

KW - atherosclerosis

KW - interleukins

KW - macrophages

KW - transcription factors

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AN - SCOPUS:85021298130

SN - 1079-5642

VL - 37

SP - 1470

EP - 1481

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 8

ER -

Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

Abstract

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