Sara Fernández-Castillejo1,2, Alba Macià3, Maria-José Motilva4, Úrsula Catalán1,2, Rosa Solà1,2,3. 1. Functional Nutrition, Oxidation, Cardiovascular Diseases Group (NFOC-Salut), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain. 2. Institut d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain. 3. Hospital Universitari Sant Joan de Reus, Reus, Spain. 4. Antioxidants Research Group, Food Technology Department, Agrotecnio Center, Universitat de Lleida, Lleida, Spain.
Abstract
SCOPE: The antithrombotic effects of resveratrol (RV) and its derivatives remain unknown. The objective is to evaluate the modulatory effects of RV, its glucoside form, piceid, and its biological metabolites (RV-3-O-β-d-glucuronide, RV-4'-O-d-glucuronide, and RV-3-O-sulfate) on tissue factor (TF). Moreover, the endothelial metabolism of RV is assessed. METHODS AND RESULTS: Human aortic endothelial cells (HAECs) are incubated with trans-piceid, trans-RV, or their biological metabolites and stimulated with tumor necrosis factor-α (TNF-α). TF activity, protein levels, and mRNA expression are determined in cell lysates. Moreover, RV conjugation (phase-II-metabolism) to its sulfated or glucuronidated metabolites and their deconjugation to their parent compound (free RV) are also assessed in cell lysates and culture media. RV decreased TF activity, protein levels, and mRNA expression, whereas piceid and RV metabolites (RVmet) had no effects. RV-3-O-sulfate was the main metabolite generated in the endothelium, while RVmet are deconjugated to free RV. Isomerization of trans-RV and its trans-metabolites to their cis-forms is observed. CONCLUSIONS: RV exerts antithrombotic effects by modulating TF. RVmet and piceid does not exert this effect. However, the capacity of endothelial cells to deconjugate RVmet to free RV indicates that RVmet function as an endothelial reservoir for RV regeneration, thus, contributing to the antithrombotic effects of RV.
SCOPE: The antithrombotic effects of resveratrol (RV) and its derivatives remain unknown. The objective is to evaluate the modulatory effects of RV, its glucoside form, piceid, and its biological metabolites (RV-3-O-β-d-glucuronide, RV-4'-O-d-glucuronide, and RV-3-O-sulfate) on tissue factor (TF). Moreover, the endothelial metabolism of RV is assessed. METHODS AND RESULTS:Human aortic endothelial cells (HAECs) are incubated with trans-piceid, trans-RV, or their biological metabolites and stimulated with tumor necrosis factor-α (TNF-α). TF activity, protein levels, and mRNA expression are determined in cell lysates. Moreover, RV conjugation (phase-II-metabolism) to its sulfated or glucuronidated metabolites and their deconjugation to their parent compound (free RV) are also assessed in cell lysates and culture media. RV decreased TF activity, protein levels, and mRNA expression, whereas piceid and RV metabolites (RVmet) had no effects. RV-3-O-sulfate was the main metabolite generated in the endothelium, while RVmet are deconjugated to free RV. Isomerization of trans-RV and its trans-metabolites to their cis-forms is observed. CONCLUSIONS:RV exerts antithrombotic effects by modulating TF. RVmet and piceid does not exert this effect. However, the capacity of endothelial cells to deconjugate RVmet to free RV indicates that RVmet function as an endothelial reservoir for RV regeneration, thus, contributing to the antithrombotic effects of RV.
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