miRNA as molecular targets of flavonoid metabolites involved in preservation of endothelial cell function

Présentation orale : Milenkovic DPrésentation orale : Milenkovic DConsumption of flavanol-rich foods is associated with a reduced risk of cardiovasculardiseases, which was linked to improvements in endothelial function. The specific flavanolsinvolved in these beneficial effects and underlying molecular mechanisms is still largelyunknown. We have shown that exposure of TNFα-activated endothelial cells to flavanolmetabolites (4’-O-methyl(−)-epicatechin, 4’-O-methyl(−)-epicatechin-7-β-D-glucuronide and(−)epicatechin-4’-sulfate) at physiologically-relevant concentrations decreased the adhesionof monocytes to endothelial monolayers. Nutrigenomic analysis showed that thesemetabolites modulate expression of genes involved in the regulation of celladhesion/junctions, focal adhesion or cytoskeleton remodeling, and this by affectingphosphorylation levels of p65 and p38 of NF-κB and MAPK cell-signaling pathwaysrespectively. Together with cell signaling pathways, microRNAs (short, endogenous,noncoding, single-stranded RNAs) represent another class of molecular post-transcriptionalregulators of gene expression. Our nutrigenomic studies have shown that exposure ofendothelial cells to the same metabolites can also modulate the expression of miRNAs.Among differentially-expressed miRNAs are those involved in the regulation of inflammationor cell adhesion, such as miR-221 and miR-181. Bioinformatic analysis shows that thepotential target genes these miRNAs are also involved in regulation of cell adhesion,cytoskeleton, focal adhesion, transendothelial migration. These miRNAs could exert posttranscriptionalregulation by inhibiting protein synthesis, as BIRC2, or by inducing mRNAdegradation, as WASP1.These data suggest that miRNAs are important molecular targets of flavanol metabolitesinvolved in the regulation of expression of genes controlling adhesion and transendothelialmigration processes. This original result contributes to increase the knowledge about themechanisms underlying the protective effect of flavanols on vascular endothelium