Epigenetic control of the angiotensin-converting enzyme in endothelial cells during inflammation

PLoS One. 2019 May 1;14(5):e0216218. doi: 10.1371/journal.pone.0216218. eCollection 2019.


The angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system, which is involved in the regulation of blood pressure. Alterations in ACE expression or activity are associated with various pathological phenotypes, particularly cardiovascular diseases. In human endothelial cells, ACE was shown to be negatively regulated by tumor necrosis factor (TNF) α. To examine, whether or not, epigenetic factors were involved in ACE expression regulation, methylated DNA immunoprecipitation and RNA interference experiments directed against regulators of DNA methylation homeostasis i.e., DNA methyltransferases (DNMTs) and ten-eleven translocation methylcytosine dioxygenases (TETs), were performed. TNFα stimulation enhanced DNA methylation in two distinct regions within the ACE promoter via a mechanism linked to DNMT3a and DNMT3b, but not to DNMT1. At the same time, TET1 protein expression was downregulated. In addition, DNA methylation decreased the binding affinity of the transcription factor MYC associated factor X to the ACE promoter. In conclusion, DNA methylation determines the TNFα-dependent regulation of ACE gene transcription and thus protein expression in human endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA Methylation / physiology
  • Endothelial Cells / enzymology*
  • Endothelial Cells / pathology
  • Epigenomics*
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / metabolism*
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Promoter Regions, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology


  • Tumor Necrosis Factor-alpha
  • ACE protein, human
  • Peptidyl-Dipeptidase A

Grants and funding

This study was supported by a grant (# 4263/2-1; to KK and IF; Exzellenzcluster 147 "Cardio-Pulmonary Systems”) from the Deutsche Forschungsgemeinschaft (http://www.dfg.de/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.