title: Flavanol metabolites reduce monocyte adhesion to endothelial cells through modulation of expression of genes via p38-MAPK and p65-Nf-kB pathways.
abstract: METHODS
  Consumption of flavanol-rich foods is associated with an improvement in endothelial function. However, the specific biologically active flavanol metabolites involved in this benefit, as well as their molecular mechanisms of action have not been identified. The aim of this work was to examine the effect of plasma flavanol metabolites on adhesion of monocytes to TNF-α-activated endothelial cells and identify potential underlying mechanisms.
  
  
  RESULTS
  4'-O-methyl(-)-epicatechin, 4'-O-methyl(-)-epicatechin-7-β-d-glucuronide, and (-)-epicatechin-4'-sulfate decreased the adhesion of monocytes to endothelial cells at physiologically relevant concentrations, from 0.2 to 1 μM. Transcriptomic studies showed that each of the flavanol metabolites affected the expression of different genes in endothelial cells. However, these genes are involved in the cellular processes that control adhesion and migration of monocytes to vascular endothelium, most notably those regulating cell adhesion, cell-cell junctions, focal adhesion, and cytoskeleton remodeling. Gene expression profiles obtained suggest lower monocyte recruitment, in agreement with results from cell adhesion assays. The nutrigenomic effect of metabolites seems to be mediated through their capacity to modulate phosphorylation of p65 and p38 cell-signaling proteins.
  
  
  CONCLUSIONS
  Our study provides findings into the molecular mechanisms by which plasma flavanol metabolites could be efficient to preserve vascular endothelium integrity in nutritionally relevant conditions.
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Claude
authors.forename: Celine
authors.initials: C
authors.lastname: Boby
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez-Mateos
authors.forename: Jeremy P E
authors.initials: JP
authors.lastname: Spencer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gérard
authors.forename: Christine
authors.initials: C
authors.lastname: Morand
authors.forename: Dragan
authors.initials: D
authors.lastname: Milenkovic
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044948:Flavonols / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D054647:Nutrigenomics / Q000379:methods; D010766:Phosphorylation; D015398:Signal Transduction; D013463:Sulfuric Acid Esters / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D044948:Flavonols; D013463:Sulfuric Acid Esters; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C452422:epicatechin sulfate; D002392:Catechin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Endothelial cells; Flavanol metabolites; Gene expression; Monocyte adhesion