Dragan Milenkovic1,2, Ana Rodriguez-Mateos3,4, Margarete Lucosz3, Geoffrey Istas3,4, Ken Declerck5, Roberto Sansone3, René Deenen6, Karl Köhrer6, Karla Fabiola Corral-Jara1, Joachim Altschmied7,8, Judith Haendeler7, Malte Kelm3, Wim Vanden Berghe5, Christian Heiss3,9,10. 1. Department of Nutrition, University of California Davis, Davis, CA, 95616, USA. 2. INRAE, UNH, Université Clermont Auvergne, Clermont-Ferrand, F-63000, France. 3. Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany. 4. Department of Nutritional Sciences, School of Life Course and Population Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK. 5. PPES, Department of Biomedical Sciences, University of Antwerp (UA), Wilrijk, Belgium. 6. Biological and Medical Research Center (BMFZ), Heinrich Heine University, Düsseldorf, Germany. 7. Environmentally-induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine University, Düsseldorf, Germany. 8. IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany. 9. Clinical Medicine Section, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. 10. Department of Vascular Medicine, Surrey and Sussex NHS Healthcare Trust, East Surrey Hospital, Redhill, UK.
Abstract
SCOPE: While cocoa flavanol (CF) consumption improves cardiovascular risk biomarkers, molecular mechanisms underlying their protective effects are not understood. OBJECTIVE: To investigate nutri(epi)genomic effects of CF and identify regulatory networks potential mediating vascular health benefits. METHODS AND RESULTS: Twenty healthy middle-aged men consume CF (bi-daily 450 mg) or control drinks for 1 month. Microarray analysis identifies 2235 differentially expressed genes (DEG) involved in processes regulating immune response, cell adhesion, or cytoskeleton organization. Distinct patterns of DEG correlate with CF-related changes in endothelial function, arterial stiffness, and blood pressure. DEG profile negatively correlates with expression profiles of cardiovascular disease patients. CF modulated DNA methylation profile of genes implicates in cell adhesion, actin cytoskeleton organization, or cell signaling. In silico docking analyses indicate that CF metabolites have the potential of binding to cell signaling proteins and transcription factors. Incubation of plasma obtained after CF consumption decrease monocyte to endothelial adhesion and dose-dependently increase nitric oxide-dependent chemotaxis of circulating angiogenic cells further validating the biological functions of CF metabolites. CONCLUSION: In healthy humans, CF consumption may mediate vascular protective effects by modulating gene expression and DNA methylation towards a cardiovascular protective effect, in agreement with clinical results, by preserving integrity of immunological-endothelial barrier functions.
SCOPE: While cocoa flavanol (CF) consumption improves cardiovascular risk biomarkers, molecular mechanisms underlying their protective effects are not understood. OBJECTIVE: To investigate nutri(epi)genomic effects of CF and identify regulatory networks potential mediating vascular health benefits. METHODS AND RESULTS: Twenty healthy middle-aged men consume CF (bi-daily 450 mg) or control drinks for 1 month. Microarray analysis identifies 2235 differentially expressed genes (DEG) involved in processes regulating immune response, cell adhesion, or cytoskeleton organization. Distinct patterns of DEG correlate with CF-related changes in endothelial function, arterial stiffness, and blood pressure. DEG profile negatively correlates with expression profiles of cardiovascular disease patients. CF modulated DNA methylation profile of genes implicates in cell adhesion, actin cytoskeleton organization, or cell signaling. In silico docking analyses indicate that CF metabolites have the potential of binding to cell signaling proteins and transcription factors. Incubation of plasma obtained after CF consumption decrease monocyte to endothelial adhesion and dose-dependently increase nitric oxide-dependent chemotaxis of circulating angiogenic cells further validating the biological functions of CF metabolites. CONCLUSION: In healthy humans, CF consumption may mediate vascular protective effects by modulating gene expression and DNA methylation towards a cardiovascular protective effect, in agreement with clinical results, by preserving integrity of immunological-endothelial barrier functions.