12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
复制标题
12-脂氧合酶活性在 PAR4 和 GPVI 介导的血小板反应性中发挥重要作用。
DOI：
10.1160/th13-01-0014
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发表时间：
2013
影响因子：
6.7
通讯作者：
Holinstat,M
中科院分区：
文献类型：
--
作者：
Yeung,J;Apopa,PL;Vesci,J;Stolla,M;Rai,G;Simeonov,A;Jadhav,A;Fernandez-Perez,P;Maloney,DJ;Boutaud,O;Holman,TR;Holinstat,M
在最初的血小板激活后，花生四烯酸由环氧合酶-1和12-脂氧合酶(12-LOX)代谢。虽然12-LOX在血小板中的作用还不是很清楚，但最近的证据表明，它可能对调节血小板的活性很重要，而且它调节血小板功能的方式是激动剂特有的。用小分子抑制剂选择性地抑制12-LOX和12-LOX缺陷小鼠，研究12-LOX对人血小板活化和血栓形成的调节作用。药物抑制12-LOX可抑制血小板聚集，选择性抑制致密颗粒与α颗粒的分泌，抑制血小板对PAR4和胶原的流动黏附。此外，与野生型小鼠相比，12-LOX缺陷小鼠对PAR4-AP和惊厥毒素的整合素活性减弱。PAR1依赖于花生四烯酸对COX-1的氧化作用，而PAR4则更依赖于12-LOX来维持正常的血小板功能。这些研究表明，12-LOX在调节血小板活化和血栓形成方面具有重要作用。此外，本文提供的数据为潜在靶向12-LOX作为减弱不必要的血小板激活和凝块形成的手段提供了基础。
Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist- specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.