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Biochem Pharmacol. 2019 Nov 20:113699. doi: 10.1016/j.bcp.2019.113699. [Epub ahead of print]

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

Author information

1
Université Clermont Auvergne, INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France; Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, United States. Electronic address: dragan.milenkovic@inra.fr.
2
PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium.
3
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
4
Université Clermont Auvergne, INRA, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
5
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, P.O. Box 616, 6200, MD, Maastricht, The Netherlands.
6
Mars, Inc., McLean, VA, United States.
7
PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium. Electronic address: Wim.vandenberghe@uantwerpen.be.

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

PMID:
31756325
DOI:
10.1016/j.bcp.2019.113699

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