Pharmacological Inhibition of Phospholipase D Protects Mice From Occlusive Thrombus Formation and Ischemic Stroke-Brief Report
Pharmacological Inhibition of Phospholipase D Protects Mice From Occlusive Thrombus Formation and Ischemic Stroke-Brief Report
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DOI：
10.1161/atvbaha.113.302030
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发表时间：
2013-09-01
影响因子：
8.7
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
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作者：
Stegner, David;Thielmann, Ina;Nieswandt, Bernhard
目的-我们最近表明，缺乏脂质信号酶磷脂酶 (PL) D1 或两种 PLD 同工型（PLD1 和 PLD2）的小鼠可以免受病理性血栓形成和缺血性中风的影响，而这些动物的止血功能并未受损。我们试图评估 PLD 活性的药理抑制是否会影响小鼠的止血、血栓形成和血栓炎症性脑梗死。方法和结果 - 使用可逆小分子 PLD 抑制剂 5-氟-2-吲哚基去氯卤代胺 (FIPI) 治疗血小板，导致 PLD 活性的特异性阻断，这与 α 颗粒释放和整合素激活减少有关。接受 3 mg/kg 剂量 FIPI 的小鼠在颈动脉或肠系膜小动脉化学损伤后表现出闭塞性血栓形成减少。同样，经过 FIPI 治疗的小鼠在短暂大脑中动脉闭塞 24 小时后梗死面积更小，运动和神经功能明显更好。这种保护作用与严重脑出血或尾部出血时间延长无关。结论-这些结果提供了第一个证据，证明药物 PLD 抑制可能提供预防动脉血栓形成和缺血性中风的安全治疗策略。
Objective-We recently showed that mice lacking the lipid signaling enzyme phospholipase (PL) D1 or both PLD isoforms (PLD1 and PLD2) were protected from pathological thrombus formation and ischemic stroke, whereas hemostasis was not impaired in these animals. We sought to assess whether pharmacological inhibition of PLD activity affects hemostasis, thrombosis, and thrombo-inflammatory brain infarction in mice.Approach and Results-Treatment of platelets with the reversible, small molecule PLD inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI), led to a specific blockade of PLD activity that was associated with reduced alpha-granule release and integrin activation. Mice that received FIPI at a dose of 3 mg/kg displayed reduced occlusive thrombus formation upon chemical injury of carotid arteries or mesenterial arterioles. Similarly, FIPI-treated mice had smaller infarct sizes and significantly better motor and neurological function 24 hours after transient middle cerebral artery occlusion. This protective effect was not associated with major intracerebral hemorrhage or prolonged tail bleeding times.Conclusions-These results provide the first evidence that pharmacological PLD inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and ischemic stroke.