Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR1 and PAR4 in platelets
Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR1 and PAR4 in platelets
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DOI：
10.1111/j.1476-5381.2009.00440.x
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Lozano, M. L.
中科院分区：
文献类型：
--
作者：
Navarro-Nunez, L.;Rivera, J.;Lozano, M. L.
背景与目的：黄酮类化合物对凝血酶诱导的血小板反应的调节研究很少，这些化合物的抗血小板活性以及对凝血酶信号传导的可能抑制机制尚未阐明。我们探讨了类黄酮是否影响血小板信号通路触发凝血酶和选择性激活其蛋白酶激活受体（PARs）1和4，并分析了这些多酚在凝血酶receptors.Experimental方法的拮抗作用：我们研究了一系列多酚化合物对血小板聚集，5-HT分泌，细胞内钙动员，蛋白激酶活性和酪氨酸磷酸化，触发凝血酶和PAR激动剂肽（PAR-AP）的影响。竞争性放射性配体结合试验使用125 I-thrombin.Key结果：槲皮素，芹菜素和染料木素受损的血小板聚集，以及5-HT释放和钙动员，诱导凝血酶和PAR-AP的能力，这些黄酮类化合物结合到凝血酶受体进行了研究。槲皮素和芹菜素是蛋白激酶的抑制剂，但染料木黄酮表现出最小的能力，抑制血小板磷酸化。结合试验没有建立任何类型的相互作用之间的凝血酶受体和任何的类黄酮tested.Conclusions和影响：槲皮素，芹菜素和染料木黄酮没有抑制凝血酶反应与凝血酶受体的相互作用，但通过干扰细胞内信号。虽然染料木黄酮的抑制作用可能是影响钙动员、随后的血小板分泌和聚集的结果，但对于槲皮素和芹菜素，激酶活化的抑制也可能参与血小板反应的损害。
Background and purpose: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.Experimental approach: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 125I-thrombin.Key results: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.Conclusions and implications: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.