Platelet-derived 12-hydroxyeicosatetraenoic acid plays an important role in mediating canine coronary thrombosis by regulating platelet glycoprotein IIb/IIIa activation
Platelet-derived 12-hydroxyeicosatetraenoic acid plays an important role in mediating canine coronary thrombosis by regulating platelet glycoprotein IIb/IIIa activation
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DOI：
10.1161/01.cir.98.25.2891
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发表时间：
1998-12-22
期刊：
影响因子：
37.8
通讯作者：
Imaizumi, T
中科院分区：
文献类型：
--
作者：
Katoh, A;Ikeda, H;Imaizumi, T
背景——在急性冠脉综合征的血栓形成过程中，血栓素 A 通过环加氧酶发挥的病理生理作用已得到充分证实。然而，12-HETE 通过 12-脂氧合酶的作用却鲜为人知。因此，我们使用 OPC-29030（一种新型 12-HETE 合成特异性抑制剂）来测试血小板衍生的 12-HETE 是否参与介导狭窄和内皮损伤的犬冠状动脉中的循环血流变化 (CFV) 和血小板聚集。 方法和结果 - 产生 CFV 后，狗静脉注射载体或 OPC-29030。 CFV、OPC-29030 后血浆和血小板内 12-HETE 水平升高，但媒介物降低的 CFV 没有升高，这与血浆和血小板内 12-HETE 水平降低相关。停止 OPC-29030 恢复 CFV 与血浆和血小板内 12-HETE 水平升高相关。 ADP 和 U46619 诱导离体血小板 12-HETE 产生和聚集。施用 OPC-29030 后，ADP 和 U46619 诱导的离体血小板 12-HETE 产生和聚集的增加受到显着抑制。血小板聚集与血小板 12-HETE 产生呈线性相关。 OPC-29030抑制人血小板糖蛋白IIb/IIIa的活化。结论-OPC-29030降低血小板内12-HETE水平，从而抑制狗体内冠状动脉血栓形成，OPC-29030在体外抑制人血小板糖蛋白IIb/IIIa活化。因此，血小板衍生的12-HETE可能在介导血栓形成过程中发挥重要作用。
Background-In the thrombotic process of acute coronary syndromes, the pathophysiological role of thromboxane A, via cyclooxygenase is well established; however, the role of 12-HETE via 12-lipoxygenase is little known. Therefore, we used OPC-29030, a novel specific inhibitor of 12-HETE synthesis, to test whether platelet-derived 12-HETE is involved in mediating cyclic flow variations (CFVs) and platelet aggregation in stenosed and endothelium-injured canine coronary arteries.Methods and Results-After developing CFVs, dogs received a vehicle or OPC-29030 intravenously. Plasma and intraplatelet 12-HETE levels increased after CFVs, OPC-29030 but not vehicle reduced CFVs, which was associated with decreases in plasma and intraplatelet 12-HETE levels, Cessation of OPC-29030 restored CFVs in association with increases in plasma and intraplatelet 12-HETE levels. ADP and U46619 induced ex vivo platelet 12-HETE production and aggregation. After OPC-29030 administration, the ADP- and U46619-induced increases in ex vivo platelet 12-HETE production and aggregation were inhibited significantly. Platelet aggregation was linearly correlated with platelet 12-HETE production. OPC-29030 suppressed activation of human platelet glycoprotein IIb/IIIa.Conclusions-OPC-29030 reduced intraplatelet 12-HETE levels, resulting in the inhibition of coronary thrombosis in vivo in dogs, OPC-29030 inhibited human platelet glycoprotein IIb/IIIa activation in vitro. Thus, platelet-derived 12-HETE may play an important role in mediating thrombotic process.