12-lipoxygenase: a potential target for novel anti-platelet therapeutics.
12-lipoxygenase: a potential target for novel anti-platelet therapeutics.
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DOI：
10.2174/187152511797037619
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发表时间：
2011-07-01
影响因子：
--
通讯作者：
Holinstat M
中科院分区：
文献类型：
--
作者：
Yeung J;Holinstat M
血小板在止血和血栓形成的调节中起着至关重要的作用，控制其活化水平是预防闭塞性血栓形成和卒中的核心。虽然已经确定了许多抗血小板靶点来解决这一问题，包括COX-1、P2Y12受体、整合素αIIbβ3，以及最近的蛋白酶激活受体-1，但这些靶点通常会导致出血风险的显著增加，这可能导致与它们原本治疗的血栓形成一样严重的病理，包括颅内出血和胃肠道出血。因此，治疗不受控制的血小板活化的替代方法是必要的。血小板型12-脂氧合酶是一种氧化血小板内游离脂肪酸产生稳定代谢物12-羟基二十碳四烯酸(12-HETE)的酶。12-HETE在血小板中的作用一直存在争议，有报道认为它既具有抗血栓作用，又具有促血栓作用。本文综述了12-脂氧合酶及其生物活性代谢产物在调节血小板反应性、凝块形成和止血中的作用。了解12-脂氧合酶及其代谢产物调节血小板功能的机制可能会导致开发一类针对该酶的新型抗血小板疗法，以减轻损伤诱导的血栓形成、血管闭塞和止血中的病理生理变化。
Platelets play an essential role in the regulation of hemostasis and thrombosis and controlling their level of activation is central to prevention of occlusive clot formation and stroke. Although a number of anti-platelet targets have been identified to address this issue including COX-1, the P2Y12 receptor, the integrin αIIbβ3, and more recently the protease-activated receptor-1, these targets often result in a significant increased risk of bleeding which may lead to pathologies as serious as the thrombosis they were meant to treat including intracranial hemorrhage and gastrointestinal bleeding. Therefore, alternative approaches to treat uncontrolled platelet activation are warranted. Platelet-type 12-lipoxygenase is an enzyme which oxidizes the free fatty acid in the platelet resulting in the production of the stable metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The role of 12-HETE in the platelet has been controversial with reports associating its function as being both anti- and pro-thrombotic. In this review, the role of 12-lipoxygenase and its bioactive metabolites in regulation of platelet reactivity, clot formation, and hemostasis is described. Understanding the mechanisms by which 12-lipoxygenase and its metabolites modulate platelet function may lead to the development of a novel class of anti-platelet therapies targeting the enzyme in order to attenuate injury-induced clot formation, vessel occlusion and pathophysiological shifts in hemostasis.