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Methylation of FOXP3 in regulatory T cells is related to the severity of coronary artery disease

  • Author Footnotes
    1 Tel.: +86 10 88398154; fax: +86 10 68331730.
    ,
    Author Footnotes
    3 Drs. Jia and Zhu contributed equally to this work.
    Lei Jia
    Footnotes
    1 Tel.: +86 10 88398154; fax: +86 10 68331730.
    3 Drs. Jia and Zhu contributed equally to this work.
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China

    The Hypertension Division, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
    Search for articles by this author
  • Author Footnotes
    2 Tel.: +86 18709275839.
    ,
    Author Footnotes
    3 Drs. Jia and Zhu contributed equally to this work.
    Ling Zhu
    Footnotes
    2 Tel.: +86 18709275839.
    3 Drs. Jia and Zhu contributed equally to this work.
    Affiliations
    Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 277 Yanta West Road, Yanta District, Xi'an 710061, Shaanxi, PR China
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  • Ji Zheng Wang
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
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  • Xiao Jian Wang
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
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  • Jing Zhou Chen
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
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  • Lei Song
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China

    The Hypertension Division, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
    Search for articles by this author
  • Yong Jian Wu
    Affiliations
    The Centre of Coronary Heart Disease, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
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  • Kai Sun
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
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  • Zu Yi Yuan
    Affiliations
    Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, No. 277 Yanta West Road, Yanta District, Xi'an 710061, Shaanxi, PR China
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  • Rutai Hui
    Correspondence
    Corresponding author. State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China. Tel.: +86 10 88398154; fax: +86 10 68331730.
    Affiliations
    Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China

    The Hypertension Division, State Key Laboratory of Translational Cardiovascular Medicine, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China
    Search for articles by this author
  • Author Footnotes
    1 Tel.: +86 10 88398154; fax: +86 10 68331730.
    2 Tel.: +86 18709275839.
    3 Drs. Jia and Zhu contributed equally to this work.

      Abstract

      Objectives

      Regulatory T (Treg) cells have been shown to play a protective role in experimental atherosclerosis. However, it is unclear whether Tregs can protect from rupture of vulnerable plaque in patients with atherosclerosis. Demethylation of the DNA encoding the transcription factor forkhead box P3 (FOXP3) was found to be essential for the stable maintenance of the suppressive properties of Tregs. We aimed to evaluate Treg levels in patients with acute coronary syndrome (ACS) using a method based on Treg-specific DNA demethylation within the FOXP3 gene.

      Methods and results

      Peripheral blood was collected to determine Treg levels by PCR-based DNA methylation analysis. We found that Treg levels were decreased in patients with ACS compared with normal coronary controls. The decrease in Tregs was associated with the severity of the ACS. Furthermore, up-regulation of DNA-methyltransferases was detected in CD4+CD25+ Tregs obtained from ACS patients as compared to those from normal coronary controls. A dose-dependent increase in the methylation of the Treg-specific demethylated region in FOXP3 was observed in cultures of PBMCs with ox-LDL. Moreover, the ox-LDL-induced Treg effects could be restored by loading (−)-epigallocatechin-3-gallate, a methyltransferase inhibitor. Treatment of CD4+CD25+ Tregs with ox-LDL resulted in a 41% increase in the methylation of FOXP3, a 66% of reduction in FOXP3 mRNA expression, and an increase in the expression of DNA methyltransferase 3a as well as 3b.

      Conclusions

      Our data demonstrate that reduction in Treg cells is associated with ACS in atherosclerotic patients. Epigenetic suppression of FOXP3 might lead to down-regulation of Treg cells, and in turn increase the risk of ACS.

      Highlights

      • We evaluate Tregs based on Treg-specific DNA demethylation within the FOXP3 gene.
      • Reduction in Treg cells is associated with ACS in atherosclerotic patients.
      • Ox-LDL suppressed the expression of FOXP3 by triggering DNA hypermethylation.
      • Epigenetic suppression of FOXP3 might down-regulate Tregs, increase the risk of ACS.

      Keywords

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