C 010: FLAVANOLS MODULATE THE TRANSCRIPTION OF GENES INVOLVED IN ATHEROSCLEROSIS WITH HETEROGENIC EPIGENETIC CHANGES OF THEIR DNA METHYLATION STATE

J Pharm Pharmacogn Res 2(Suppl. 1): S29, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 010: FLAVANOLS MODULATE THE TRANSCRIPTION OF GENES INVOLVED IN ATHEROSCLEROSIS WITH HETEROGENIC EPIGENETIC CHANGES OF THEIR DNA METHYLATION STATE

Weseler AR1, Milenkovic D2, Szarcvel Szic K3, Declerck K3, Heyninck K4, Haegeman G4, Haenen GRMM1, Bast A1, Fuks F5, Gerhauser C6, Vanden Berghe W3,4 .

1Maastricht University, The Netherlands.
2INRA Research Centre Clermont-Ferrand/Theix, France.
3University of Antwerp, Belgium. E-mail: wim.vandenberghe@ua.ac.be
4University of Gent, Belgium.
5Free University of Brussels, Belgium  6DKFZ Heidelberg, Germany.
Abstract

Epidemiological studies show that a flavanol-rich diet (cocoa, grape) is associated with a decreased risk of cardiovascular disease (CVD). In how far biological effects occur in endothelial HUVEC cells exposed to flavanols in vitro or in humans upon flavanol supplementation is yet unclear. In the Flaviola-consortium (www.flaviola.org), potential biological processes modified by flavanols were evaluated at the transcriptomic and epigenomic levelin HUVEC cells exposed to specific flavanol metabolites or in leukocyte samples collected from diet intervention studies. In vitro experiments in HUVEC cells demonstrate that flavanols significantly decrease monocyte cell adhesion, concomitantly with changes in gene expression and DNA methylation in cell adhesion pathways. Furthermore, in a randomized, double-blind, placebo controlled trial, healthy male smokers supplemented for 8 weeks with 200 mg/d oligomeric flavanols, unveiled pleiotropic vascular health benefit by an integrative multi-biomarker approach (PLoS One. 2011;6(12):e28460.).Gene expression analysis via cDNA microarrays (Agilent 4x44Kv2) further revealed significant changes in various cellular processes like chemotaxis, cell adhesion, cell infiltration and cytoskeleton organization. Regarding DNA methylation changes measured by Illumina 450K CpG array, heterogenic responses were observed in gene clusters involved in detoxification, metabolism and cell adhesion. Although the intervention triggered significant changes in DNA methylation levels (>10%) of 0.2-1% of the methylome (450.000 CGI) at the individual level, no common flavanol-specific DNA methylation response of specific target genes involved in CVD could be identified at the cohort level. Interestingly, strong interindividual variability in DNA methylation levels of detoxification and metabolisation genes can be linked to long-term smoking history, which may overrule diet specific effects of an 8 week diet intervention. Altogether, flavanols may elicit cardioprotective effects by decreasing cell adhesion pathways at the transcriptomic and epigenomic level. Furthermore, smoking history may be a confounding factor in epigenetic profiling studies of leucocytes from subjects involved in a flavanol diet intervention.