Antiplatelet properties of Pim kinase inhibition are mediated through disruption of thromboxane A2 receptor signaling.
Antiplatelet properties of Pim kinase inhibition are mediated through disruption of thromboxane A2 receptor signaling.
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DOI：
10.3324/haematol.2019.223529
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发表时间：
2021-07-01
期刊：
影响因子：
10.1
通讯作者：
Gibbins JM
中科院分区：
文献类型：
--
作者：
Unsworth AJ;Bye AP;Sage T;Gaspar RS;Eaton N;Drew C;Stainer A;Kriek N;Volberding PJ;Hutchinson JL;Riley R;Jones S;Mundell SJ;Cui W;Falet H;Gibbins JM
PIM激酶在几种形式的癌症中表达上调，有助于细胞存活和肿瘤发展，但它们在血小板功能和血栓性疾病中的作用尚未被探索。我们首次报道了Pim-1激酶在人和小鼠血小板中的表达。Pim激酶的基因缺失或药物抑制会导致血栓形成减少，但与止血功能受损无关。血栓形成的减弱被发现是由于血栓素A2受体的抑制，因为对血小板功能的影响与环氧合酶抑制剂吲哚美辛或血栓素A2受体拮抗剂GR32191引起的抑制非相加。用Pim激酶抑制剂处理后，血栓素A2受体的表面表达减少，对血栓素A2受体激动剂的反应性降低，表明Pim激酶在调节血栓素A2受体功能中起作用。我们的研究确定了一种新的、依赖于Pim激酶的血栓素A2受体调节机制，并代表了一种新的靶向策略，该策略不依赖于对血栓素A2受体的环氧合酶-1抑制或直接拮抗，虽然可以减轻血栓形成，但不会增加出血。
Pim kinases are upregulated in several forms of cancer, contributing to cell survival and tumor development, but their role in platelet function and thrombotic disease has not been explored. We report for the first time that Pim-1 kinase is expressed in human and mouse platelets. Genetic deletion or pharmacological inhibition of Pim kinase results in reduced thrombus formation but is not associated with impaired hemostasis. Attenuation of thrombus formation was found to be due to inhibition of the thromboxane A2 receptor as effects on platelet function were non-additive to inhibition caused by the cyclo-oxygenase inhibitor indomethacin or the thromboxane A2 receptor antagonist GR32191. Treatment with Pim kinase inhibitors caused reduced surface expression of the thromboxane A2 receptor and resulted in reduced responses to thromboxane A2 receptor agonists, indicating a role for Pim kinase in the regulation of thromboxane A2 receptor function. Our research identifies a novel, Pim kinase-dependent regulatory mechanism for the thromboxane A2 receptor and represents a new targeting strategy that is independent of cyclo-oxygenase-1 inhibition or direct antagonism of the thromboxane A2 receptor that, while attenuating thrombosis, does not increase bleeding.