Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U596, Centre National de la Recherche Scientifique UMR7104, Université Louis Pasteur, 67400 Illkirch, France.
Cardiovasc Res. 2014 Mar 1;101(3):482-91. doi: 10.1093/cvr/cvt276. Epub 2013 Dec 9.
Haemostasis interrupts bleeding from disrupted blood vessels by activating platelet aggregation and coagulation. A similar mechanism termed thrombosis generates obstructive thrombi inside diseased arteries. As a consequence of this similarity, current anti-thrombotic agents increase the risk of bleeding. Atherosclerotic plaques produce significant amounts of prostaglandin E2 (PGE2), which activates its receptor EP3 on platelets and aggravates atherothrombosis. We investigated whether blocking EP3 could dissociate atherothrombosis from haemostasis.
Inhibiting in vivo the receptor EP3 for PGE2 with the blocking agent DG-041 reduced murine thrombosis triggered by local delivery of arachidonic acid or ferric chloride on healthy arteries. Importantly, it also reduced thrombosis triggered by scratching murine atherosclerotic plaques. PGE2 was not produced at the bleeding site after tail clipping. Consistently, blocking EP3 did not alter murine tail, liver, or cerebral haemostasis. Furthermore, blocking EP3 reduced murine pulmonary embolism and intensified platelet inhibition by clopidogrel leaving tail bleeding times unchanged. Human atherosclerotic plaques produced PGE2, which facilitated platelet aggregation in human blood and rescued the function of P2Y12-blocked platelets. Finally, in healthy patients, DG-041 reduced platelet aggregation, but did not significantly alter the cutaneous bleeding time at doses up to eight times the dose that inhibited the facilitating effect of PGE2 on platelets.
In mice, blocking EP3 inhibited atherothrombosis without affecting haemostasis and intensified efficiency of conventional anti-platelet treatment without aggravating the bleeding risk. In patients, blocking EP3 should improve the prevention of cardiovascular diseases, which is currently limited by the risk of bleeding.
止血通过激活血小板聚集和凝血来阻止受损血管的出血。类似的机制——血栓形成——在病变动脉内部产生阻塞性血栓。由于这种相似性，目前的抗血栓药物会增加出血的风险。动脉粥样硬化斑块会产生大量的前列腺素 E2（PGE2），它会激活血小板上的 EP3 受体，加重动脉粥样血栓形成。我们研究了阻断 EP3 是否可以将动脉粥样血栓形成与止血分离。
用阻断剂 DG-041 抑制体内 PGE2 的受体 EP3，可减少健康动脉局部给予花生四烯酸或氯化铁后引发的小鼠血栓形成。重要的是，它还减少了对小鼠动脉粥样硬化斑块划痕引发的血栓形成。在剪尾后出血部位没有产生 PGE2。一致地，阻断 EP3 并没有改变小鼠尾巴、肝脏或大脑的止血功能。此外，阻断 EP3 减少了小鼠肺栓塞，并增强了氯吡格雷对血小板的抑制作用，而不改变尾巴出血时间。人类动脉粥样硬化斑块产生 PGE2，促进人血液中的血小板聚集，并挽救了 P2Y12 阻断血小板的功能。最后，在健康患者中，DG-041 减少了血小板聚集，但在高达抑制 PGE2 对血小板的促进作用剂量的 8 倍的剂量下，并没有显著改变皮肤出血时间。
在小鼠中，阻断 EP3 抑制了动脉粥样血栓形成，而不影响止血功能，并增强了常规抗血小板治疗的效果，而不会增加出血风险。在患者中，阻断 EP3 应该改善心血管疾病的预防，目前这受到出血风险的限制。
