Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR(1) and PAR(4) in platelets

The modulation by flavonoids of platelet responses induced by thrombin has been little investigated, and the antiplatelet activity, as well as possible inhibitory mechanisms of these compounds on thrombin signalling, has not yet been elucidated. We explored whether flavonoids affect platelet signall...

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Bibliographic Details
Published in:British journal of pharmacology 2009-11, Vol.158 (6), p.1548-1556
Main Authors: Navarro-Núñez, L, Rivera, J, Guerrero, J A, Martínez, C, Vicente, V, Lozano, M L
Format: Article
Language:English
Subjects:
Apigenin - pharmacology
Calcium - metabolism
Flavonoids - pharmacology
Genistein - pharmacology
Humans
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - pharmacology
Quercetin - pharmacology
Radioligand Assay
Receptor, PAR-1 - drug effects
Receptor, PAR-1 - metabolism
Receptors, Thrombin - drug effects
Receptors, Thrombin - metabolism
Serotonin - metabolism
Signal Transduction - drug effects
Thrombin - metabolism
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Summary:The modulation by flavonoids of platelet responses induced by thrombin has been little investigated, and the antiplatelet activity, as well as possible inhibitory mechanisms of these compounds on thrombin signalling, has not yet been elucidated. We explored whether flavonoids affect platelet signalling pathways triggered by thrombin and by the selective activation of its protease-activated receptors (PARs) 1 and 4, and analysed the antagonism of these polyphenols at thrombin receptors. We investigated the effect of a range of polyphenolic compounds on platelet aggregation, 5-HT secretion, intracellular calcium mobilization, protein kinase activity and tyrosine phosphorylation, triggered by thrombin and PAR agonist peptides (PAR-APs). The ability of these flavonoids to bind to thrombin receptors was investigated by competitive radioligand binding assays using (125)I-thrombin. Quercetin, apigenin and genistein impaired platelet aggregation, as well as 5-HT release and calcium mobilization, induced by thrombin and PAR-APs. Quercetin and apigenin were inhibitors of protein kinases, but genistein exhibited a minimal ability to suppress platelet phosphorylation. Binding assays did not establish any kind of interaction between thrombin receptors and any of the flavonoids tested. Quercetin, apigenin and genistein did not inhibit thrombin responses by interacting with thrombin receptors, but by interfering with intracellular signalling. While inhibition by genistein may be a consequence of affecting calcium mobilization, subsequent platelet secretion and aggregation, for quercetin and apigenin, inhibition of kinase activation may also be involved in the impairment of platelet responses.
ISSN:1476-5381
DOI:10.1111/j.1476-5381.2009.00440.x