Abstract
Although vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood. The aim of this study was to characterize the potential endothelium-protective effects of circulating epicatechin metabolites and to define underlying mechanisms of action by an integrated systems biology approach. Reduced leukocyte rolling over vascular endothelium was observed following epicatechin supplementation in a mouse model of inflammation. Integrative pathway analysis of transcriptome, miRNome and epigenome profiles of endothelial cells exposed to epicatechin metabolites revealed that by acting at these different levels of regulation, metabolites affect cellular pathways involved in endothelial permeability and interaction with immune cells. In-vitro experiments on endothelial cells confirmed that epicatechin metabolites reduce monocyte adhesion and their transendothelial migration. Altogether, our in-vivo and in-vitro results support the outcome of a systems biology based network analysis which suggests that epicatechin metabolites mediate their vasculoprotective effects through dynamic regulation of endothelial cell monocyte adhesion and permeability. This study illustrates complex and multimodal mechanisms of action by which epicatechin modulate endothelial cell integrity.
Highlights
Vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood
To obtain proof of concept for in vivo efficacy of flavan-3-ols, we evaluated the effect of a 7-day dietary supplementation with epicatechin, 0.06 g/kg of diet, on leukocyte rolling in a mouse model of vascular inflammation
To elucidate the mechanism of action, we applied a systems biology approach utilizing transcriptome, miRNome and epigenome data obtained in human endothelial cells exposed to physiologically-relevant concentrations of the epicatechin metabolites identified in plasma after the consumption of epicatechin-rich foods
Summary
Vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood. Flavan-3-ols represent a major group of flavonoids found in the Western diets and include monomeric, oligomeric and polymeric forms of catechin (C) and epicatechin (EC) These compounds are found in most foods and are abundant in cocoa, green tea, red wine and various fruits. We have previously shown that the exposure of endothelial cells to individual sulfate, glucuronide and methyl-glucuronide derivatives of EC, used in a physiological range of concentrations, decreased monocyte adhesion to TNFα-activated endothelial cells[13] This effect was observed together with the ability of these EC metabolites to modulate endothelial expression of a large set of genes that are involved in cell processes regulating monocyte adhesion and transmigration across the vascular wall. Cocoa flavan-3-ols have been shown to modulate DNA methylation of peripheral leukocytes in humans[20,21,22]
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