Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway
Sulforaphane prevents human platelet aggregation through inhibiting the phosphatidylinositol 3-kinase/Akt pathway
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DOI：
10.1160/th12-09-0636
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发表时间：
2013-06-01
影响因子：
6.7
通讯作者：
Wu, Chin-Chung
中科院分区：
文献类型：
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作者：
Chuang, Wen-Ying;Kung, Po-Hsiung;Wu, Chin-Chung
萝卜硫素是一种在十字花科蔬菜中发现的膳食异硫氰酸盐，已被证明对心血管疾病的动物模型有有益作用。然而，其对血小板聚集的影响尚不清楚，而血小板聚集是动脉血栓形成的关键因素。在本研究中，我们发现萝卜硫素抑制由不同受体激动剂引起的人血小板聚集，包括胶原蛋白、U46619（一种血栓素a(2)模拟物）、蛋白酶激活受体1激动剂肽（PAR1-AP）和ADP P2Y（12）受体激动剂。此外，在全血流动条件下，萝卜硫素显著减少了胶原包被表面的血栓形成。在探索其潜在机制时，我们发现萝卜硫素特异性地阻止磷脂酰肌醇3-激酶(PI3K)/Akt信号传导，而不会显著影响其他参与血小板聚集的信号通路，如蛋白激酶C激活、钙动员和蛋白酪氨酸磷酸化。虽然萝卜硫素不直接抑制PI3K的催化活性，但它引起PI3K的调控亚基p85泛素化，阻止PI3K转运到膜上。此外，萝卜硫素引起磷酸化肌苷依赖性激酶1 （phosphoinosiide -dependent kinase 1, PDK1）的泛素化和降解，而PDK1是Akt活化所必需的。因此，萝卜硫素能够在两个不同的位点抑制PI3K/Akt通路。总之，我们已经证明，萝卜硫素阻止血小板聚集和减少血栓形成的流动条件；我们的数据还支持萝卜硫素抑制PI3K/Akt通路有助于其抗血小板作用。
Sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, has been shown to exert beneficial effects in animal models of cardiovascular diseases. However, its effect on platelet aggregation, which is a critical factor in arterial thrombosis, is still unclear. In the present study, we show that sulforaphane inhibited human platelet aggregation caused by different receptor agonists, including collagen, U46619 (a thromboxane A(2) mimic), protease-activated receptor 1 agonist peptide (PAR1-AP), and an ADP P2Y(12) receptor agonist. Moreover, sulforaphane significantly reduced thrombus formation on a collagen-coated surface under whole blood flow conditions. In exploring the underlying mechanism, we found that sulforaphane specifically prevented phosphatidylinositol 3-kinase (PI3K)/Akt signalling, without markedly affecting other signlaling pathways involved in platelet aggregation, such as protein kinase C activation, calcium mobilisation, and protein tyrosine phosphorylation. Although sulforaphane did not directly inhibit the catalytic activity of PI3K, it caused ubiquitination of the regulatory p85 subunit of PI3K, and prevented PI3K translocation to membranes. In addition, sulforaphane caused ubiquitination and degradation of phosphoinositide-dependent kinase 1 (PDK1), which is required for Akt activation. Therefore, sulforaphane is able to inhibit the PI3K/Akt pathway at two distinct sites. In conclusion, we have demonstrated that sulforaphane prevented platelet aggregation and reduced thrombus formation in flow conditions; our data also support that the inhibition of the PI3K/Akt pathway by sulforaphane contributes it antiplatelet effects.