IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis

被引：78

作者：

Chen, Hsiao-Huei ^{[1
,2
,5
]}

Keyhanian, Kianoosh ^{[1
,2
]}

Zhou, Xun ^{[1
,2
]}

Vilmundarson, Ragnar O. ^{[3
,4
]}

Almontashiri, Naif A. M. ^{[3
,4
]}

Cruz, Shelly A. ^{[1
,2
]}

Pandey, Nihar R. ^{[1
,2
]}

Yap, Nida Lerma ^{[3
,4
]}

Ho, Tiffany ^{[3
,4
]}

Stewart, Chloe A. ^{[1
,2
]}

Huang, Hua ^{[1
,2
]}

Hari, Aswin ^{[1
,2
]}

Geoffrion, Michele ^{[3
,4
]}

McPherson, Ruth ^{[3
,4
,5
]}

Rayner, Katey J. ^{[3
,4
]}

Stewart, Alexandre F. R. ^{[3
,4
,5
]}

机构：

[1] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada

[2] Ottawa Hosp, Res Inst, Ottawa, ON, Canada

[3] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada

[4] Univ Ottawa, Inst Heart, Ottawa, ON, Canada

[5] Univ Ottawa, Dept Med, Ottawa, ON, Canada

来源：

CIRCULATION RESEARCH | 2015年 / 117卷 / 08期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

3 untranslated region; atherosclerosis; cholesterol; coronary artery disease; genetics; macrophages; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; GENE-EXPRESSION; REGULATORY FACTOR-2; MEF2; KLF2; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION; POLARIZATION;

D O I：

10.1161/CIRCRESAHA.114.305777

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Rationale: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. Objectives: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. Methods and Results: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Kruppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Kruppel-like factor 2. Importantly, restoring Kruppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3 untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Kruppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. Conclusion: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.

引用

页码：671 / 683

页数：13

共 38 条

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Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates α1-adrenergic activation of gene expression in cardiac myocytes [J].