Dietary flavanols modulate the transcription of genes associated with cardiovascular pathology without changes in their DNA methylation state.
BACKGROUND
In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation.


RESULTS
Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found.


CONCLUSIONS
Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans.
INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France.
Dragan
D
Milenkovic
Laboratory of Eukaryotic Gene Expression and Signal Transduction LEGEST, University of Gent, Gent, Belgium; PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium.
Wim
W
Vanden Berghe
INRA, UMR1213 Herbivores, Plate-Forme d'Exploration du Métabolisme, Saint-Genès-Champanelle, France.
Céline
C
Boby
INRA, UMR1213 Herbivores, Plate-Forme d'Exploration du Métabolisme, Saint-Genès-Champanelle, France.
Christine
C
Leroux
PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium.
Ken
K
Declerck
PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium.
Katarzyna
K
Szarc vel Szic
Laboratory of Eukaryotic Gene Expression and Signal Transduction LEGEST, University of Gent, Gent, Belgium.
Karen
K
Heyninck
Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium; Biomedical Informatics Research Center Antwerp (Biomina), University of Antwerp/Antwerp University Hospital, Edegem, Belgium.
Kris
K
Laukens
Laboratory of Cancer Epigenetics, Free University of Brussels, Brussels, Belgium.
Martin
M
Bizet
Laboratory of Cancer Epigenetics, Free University of Brussels, Brussels, Belgium.
Matthieu
M
Defrance
Laboratory of Cancer Epigenetics, Free University of Brussels, Brussels, Belgium.
Sarah
S
Dedeurwaerder
Laboratory of Cancer Epigenetics, Free University of Brussels, Brussels, Belgium.
Emilie
E
Calonne
Laboratory of Cancer Epigenetics, Free University of Brussels, Brussels, Belgium.
Francois
F
Fuks
Laboratory of Eukaryotic Gene Expression and Signal Transduction LEGEST, University of Gent, Gent, Belgium.
Guy
G
Haegeman
Department of Toxicology, Maastricht University, MD Maastricht, Netherlands.
Guido R M M
GR
Haenen
Department of Toxicology, Maastricht University, MD Maastricht, Netherlands.
Aalt
A
Bast
Department of Toxicology, Maastricht University, MD Maastricht, Netherlands.
Antje R
AR
Weseler
D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D018899:CpG Islands; D019175:DNA Methylation; D005419:Flavonoids / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D056604:Grape Seed Extract / Q000008:administration & dosage*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000187:drug effects*; D059467:Transcriptome
D005419:Flavonoids; D056604:Grape Seed Extract; D016328:NF-kappa B