Michael Holinstat, Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, 1020 Locust Street, Suite 394, Jefferson Alumni Hall, Philadelphia, PA, USA, Tel.: +1 215 955 6121, Fax: +1 215 955 9170, E-mail:
Thromb Haemost. 2013 Sep;110(3):569-81. doi: 10.1160/TH13-01-0014. Epub 2013 Jun 20.
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.
血小板最初被激活后，花生四烯酸被环氧化酶-1 和 12-脂氧合酶（12-LOX）代谢。虽然 12-LOX 在血小板中的作用尚未明确，但最近的证据表明，它可能对调节血小板活性很重要，并且在调节血小板功能的方式上具有激动剂特异性。使用针对 12-LOX 的小分子抑制剂和 12-LOX 缺陷小鼠，研究了 12-LOX 在调节人血小板激活和血栓形成中的作用。药理抑制 12-LOX 导致血小板聚集减弱，致密颗粒与 α 颗粒分泌的选择性抑制，以及 PAR4 和胶原蛋白下的血小板在流动中的黏附抑制。此外，与野生型小鼠相比，12-LOX 缺陷型小鼠对 PAR4-AP 和 convulxin 的整合素活性减弱。最后，PAR 激活被证明对 COX-1 和 12-LOX 的依赖性不同，PAR1 依赖 COX-1 氧化花生四烯酸，而 PAR4 则更依赖 12-LOX 来维持正常的血小板功能。这些研究表明 12-LOX 在调节血小板激活和血栓形成中起着重要作用。此外，这里提供的数据为靶向 12-LOX 作为减轻不必要的血小板激活和血栓形成的手段提供了基础。
