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

Biochem Pharmacol. 2020 Mar;173:113699. doi: 10.1016/j.bcp.2019.113699. Epub 2019 Nov 20.

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.

Keywords: Endothelial-immune cell signaling; Epicatechin metabolite; Epigenetic; Systemic low-grade inflammation; Vascular health.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catechin / chemistry
  • Catechin / metabolism
  • Catechin / pharmacology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • DNA (Cytosine-5-)-Methyltransferases / chemistry
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / drug effects
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Epigenesis, Genetic / drug effects*
  • Gene Expression Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • Molecular Docking Simulation
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Oxidative Stress / drug effects
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Transendothelial and Transepithelial Migration / drug effects
  • Transendothelial and Transepithelial Migration / genetics

Substances

  • Catechin
  • DNA (Cytosine-5-)-Methyltransferases