title: Methylation of FOXP3 in regulatory T cells is related to the severity of coronary artery disease.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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. jialei27@gmail.com
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.forename: Ji Zheng
authors.initials: JZ
authors.lastname: Wang
authors.forename: Xiao Jian
authors.initials: XJ
authors.lastname: Wang
authors.forename: Jing Zhou
authors.initials: JZ
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Yong Jian
authors.initials: YJ
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Zu Yi
authors.initials: ZY
authors.lastname: Yuan
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D000704:Analysis of Variance; D016022:Case-Control Studies; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D008077:Lipoproteins, LDL; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C418974:FOXP3 protein, human; C099252:oxidized low density lipoprotein