Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization

被引：43

作者：

Bai, Liang ^{[1
,2
,3
,4
]}

Li, Zhao ^{[4
]}

Li, Qianwei ^{[1
,2
,3
]}

Guan, Hua ^{[1
,2
,3
]}

Zhao, Sihai ^{[1
,2
,3
]}

Liu, Ruihan ^{[1
,2
,3
]}

Wang, Rong ^{[1
,2
,3
]}

Zhang, Jin ^{[4
]}

Jia, Yuzhi ^{[5
]}

Fan, Jianglin ^{[6
]}

Wang, Nanping ^{[4
]}

Reddy, Janardan K. ^{[5
]}

Shyy, John Y. -J. ^{[4
,7
]}

Liu, Enqi ^{[1
,2
,3
]}

机构：

[1] Xi An Jiao Tong Univ, Hlth Sci Ctr, Res Inst Atherosclerot Dis, Xian 710061, Shaanxi, Peoples R China

[2] Xi An Jiao Tong Univ, Key Lab Environm & Genes Related Dis, Minist Educ China, Xian, Shaanxi, Peoples R China

[3] Xi An Jiao Tong Univ, Hlth Sci Ctr, Lab Anim Ctr, Xian, Shaanxi, Peoples R China

[4] Xi An Jiao Tong Univ, Hlth Sci Ctr, Cardiovasc Res Ctr, Sch Basic Med Sci, Xian, Shaanxi, Peoples R China

[5] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA

[6] Univ Yamanashi, Interdisciplinary Grad Sch Med & Engn, Dept Mol Pathol, Kofu, Yamanashi, Japan

[7] Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA 92093 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2017年 / 37卷 / 08期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

apolipoproteins; atherosclerosis; interleukins; macrophages; transcription factors; PROLIFERATOR-ACTIVATED RECEPTOR; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; DEFICIENT MICE; PPAR-ALPHA; GAMMA; PROTEIN; CELLS; INFLAMMATION; KNOCKOUT;

D O I：

10.1161/ATVBAHA.117.309672

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1470 / 1481

页数：12

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