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外文期刊>The biochemical journal
>Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways
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Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways
pPI3Ks (phosphoinositide 3-kinases) play a critical role in platelet functional responses. PI3Ks are activated upon P2Ysub12/sub receptor stimulation and generate pro-aggregatory signals. P2Ysub12/sub receptor has been shown to play a key role in the platelet aggregation and thromboxane Asub2/sub generation caused by co-stimulation with Gsubq/sub or Gsubz/sub, or super-stimulation of Gsubi/sub pathways. In the present study, we evaluated the role of specific PI3K isoforms α, β, γ and δ in platelet aggregation, thromboxane Asub2/sub generation and ERK (extracellular-signal-regulated kinase) activation. Our results show that loss of the PI3K signal impaired the ability of ADP to induce platelet aggregation, ERK phosphorylation and thromboxane Asub2/sub generation. We also show that Gsubq/sub plus Gsubi/sub- or Gsubi/sub plus Gsubz/sub-mediated platelet aggregation, ERK phosphorylation and thromboxane Asub2/sub generation in human platelets was inhibited by TGX-221, a PI3Kβ-selective inhibitor, but not by PIK75 (a PI3Kα inhibitor), AS252424 (a PI3Kγ inhibitor) or IC87114 (a PI3Kδ inhibitor). TGX-221 also showed a similar inhibitory effect on the Gsubi/sub plus Gsubz/sub-mediated platelet responses in platelets from P2Ysub1/subsup?/?/sup mice. Finally, 2MeSADP (2-methyl-thio-ADP)-induced Akt phosphorylation was significantly inhibited in the presence of TGX-221, suggesting a critical role for PI3Kβ in Gsubi/sub-mediated signalling. Taken together, our results demonstrate that PI3Kβ plays an important role in ADP-induced platelet aggregation. Moreover, PI3Kβ mediates ADP-induced thromboxane Asub2/sub generation by regulating ERK phosphorylation./p
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机译：p3Ks（磷酸肌醇3激酶）在血小板功能反应中起关键作用。 PI3Ks在P2Y 12 受体刺激下被激活并产生促聚集信号。已显示P2Y 12 受体在与G q 共同刺激引起的血小板聚集和血栓烷A 2 产生中起关键作用G z 或G i 通路的超刺激。在本研究中，我们评估了特定的PI3K亚型α，β，γ和δ在血小板聚集，血栓烷A 2 生成和ERK（细胞外信号调节激酶）活化中的作用。我们的结果表明，PI3K信号的缺失会损害ADP诱导血小板聚集，ERK磷酸化和血栓烷A 2 生成的能力。我们还显示G q 加G i -或G i 加G z 介导的血小板聚集，ERK PI3Kβ选择性抑制剂TGX-221抑制人血小板中的磷酸化和血栓烷A 2 产生，PIK75（PI3Kα抑制剂），AS252424（PI3Kγ抑制剂）或IC87114（PI3Kδ）抑制抑制剂）。 TGX-221对P2Y 1 ？血小板中的G i 和G z 介导的血小板反应也显示出相似的抑制作用。 /？小鼠。最后，在TGX-221的存在下，2MeSADP（2-甲基-硫代-ADP）诱导的Akt磷酸化被显着抑制，表明PI3Kβ在G i 介导的信号传导中起关键作用。两者合计，我们的结果表明PI3Kβ在ADP诱导的血小板聚集中起重要作用。此外，PI3Kβ通过调节ERK的磷酸化介导ADP诱导的血栓烷A 2 的产生。
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