(-)-Epicatechin metabolites promote vascular health through epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation

Dragan Milenkovic*, Ken Declerck, Yelena Guttman, Zohar Kerem, Sylvain Claude, Antje R Weseler, Aalt Bast, Hagen Schroeter, Christine Morand, Wim Vanden Berghe*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

Abstract

Ingestion of (-)-epicatechin flavanols reverses endothelial dysfunction by increasing flow mediated dilation and by reducing vascular inflammation and oxidative stress, monocyte-endothelial cell adhesion and transendothelial monocyte migration in vitro and in vivo. This involves multiple changes in gene expression and epigenetic DNA methylation by poorly understood mechanisms. By in silico docking and molecular modeling we demonstrate favorable binding of different glucuronidated, sulfated or methylated (-)-epicatechin metabolites to different DNA methyltransferases (DNMT1/DNMT3A). In favor of this model, genome-wide DNA methylation profiling of endothelial cells treated with TNF and different (-)-epicatechin metabolites revealed specific DNA methylation changes in gene networks controlling cell adhesion-extravasation endothelial hyperpermeability as well as gamma-aminobutyric acid, renin-angiotensin and nitric oxide hypertension pathways. Remarkably, blood epigenetic profiles of an 8 weeks intervention with monomeric and oligomeric flavanols (MOF) including (-)-epicatechin in male smokers revealed individual epigenetic gene changes targeting similar pathways as the in vitro exposure experiments in endothelial cells. Furthermore, epigenetic changes following MOF diet intervention oppose atherosclerosis associated epigenetic changes. In line with biological data, the individual epigenetic response to a MOF diet is associated with different vascular health parameters (glutathione peroxidase 1 and endothelin-1 expression, acetylcholine-mediated microvascular response), in part involving systemic shifts in blood immune cell types which reduce the neutrophil-lymphocyte ratio (NLR). Altogether, our study suggests that different (-)-epicatechin metabolites promote vascular health in part via epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation.

Original languageEnglish
Article number113699
Number of pages16
JournalBiochemical Pharmacology
Volume173
DOIs
Publication statusPublished - Mar 2020

Keywords

  • Epicatechin metabolite
  • Vascular health
  • Epigenetic
  • Endothelial-immune cell signaling
  • Systemic low-grade inflammation
  • INTRAGENIC DNA METHYLATION
  • C-REACTIVE PROTEIN
  • LYMPHOCYTE RATIO
  • OXIDATIVE STRESS
  • COCOA FLAVANOLS
  • BLOOD-PRESSURE
  • CHOCOLATE
  • RISK
  • HOMOCYSTEINE
  • FLAVONOIDS

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