Tourdot Benjamin E, Adili Reheman, Isingizwe Zitha R, Ebrahem Meral, Freedman J Cody, Holman Theodore R, Holinstat Michael
Department of Pharmacology, University of Michigan, Ann Arbor, MI.
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA; and.
Blood Adv. 2017 Jun 23;1(15):1124-1131. doi: 10.1182/bloodadvances.2017006155. eCollection 2017 Jun 27.
The dihomo-γ-linolenic acid (DGLA)-derived metabolite of 12-lipoxygenase, 12-hydroxy-eicosatrienoic acid (12-HETrE), was recently shown to potently inhibit thrombus formation without prolonging bleeding in murine models. Although 12-HETrE was found to inhibit platelet activation via the Gα signaling pathway, the Gα-coupled receptor by which 12-HETrE mediates its antiplatelet effects has yet to be identified. Defining the receptor by which 12-HETrE exerts its effects is key to determining its therapeutic potential as an antiplatelet drug. Therefore, the goal of this study was to determine the Gα-coupled platelet receptor through which 12-HETrE exerts its antiplatelet effects. In this study, we showed that pharmacological inhibition of the prostacyclin (IP) receptor in human platelets or genetic ablation of IP in murine platelets prevented 12-HETrE from blocking aggregation in vitro. Furthermore, the antithrombotic effects of 12-HETrE were significantly diminished in IP knockout mice in vivo. Together these data demonstrate that the antiplatelet effects of 12-HETrE are at least partially dependent on IP signaling. Importantly, this work identified 12-HETrE as a novel regulator of IP signaling that may aid in the rationale for design of novel therapeutics to inhibit platelet function. Additionally, this study provides further insight into the mechanism by which DGLA supplementation inhibits platelets function.
12-脂氧合酶的二高-γ-亚麻酸（DGLA）衍生代谢产物12-羟基二十碳三烯酸（12-HETrE）最近在小鼠模型中显示出能有效抑制血栓形成且不延长出血时间。尽管发现12-HETrE通过Gα信号通路抑制血小板活化，但12-HETrE介导其抗血小板作用的Gα偶联受体尚未确定。确定12-HETrE发挥作用的受体是确定其作为抗血小板药物治疗潜力的关键。因此，本研究的目的是确定12-HETrE发挥抗血小板作用所通过的Gα偶联血小板受体。在本研究中，我们表明对人血小板中前列环素（IP）受体的药理抑制或小鼠血小板中IP的基因敲除可阻止12-HETrE在体外阻断聚集。此外，12-HETrE的抗血栓作用在体内IP基因敲除小鼠中显著减弱。这些数据共同表明12-HETrE的抗血小板作用至少部分依赖于IP信号传导。重要的是，这项工作确定12-HETrE是IP信号传导的新型调节剂，这可能有助于为设计抑制血小板功能的新型疗法提供理论依据。此外，本研究进一步深入了解了补充DGLA抑制血小板功能的机制。
