Dai Jianping, Louedec Liliane, Philippe Monique, Michel Jean-Baptiste, Houard Xavier
INSERM U698, Cardiovascular Haematology, Bio-Engineering and Remodeling, Bichat-Claude Bernard Hospital, Paris, France.
J Vasc Surg. 2009 Mar;49(3):719-27. doi: 10.1016/j.jvs.2008.09.057. Epub 2008 Nov 22.
Platelet activation and thrombus renewal are keys to intraluminal thrombus formation and progression of abdominal aortic aneurysms (AAA). This study explored the ability of AZD6140, a P2Y(12) receptor antagonist, to inhibit platelet activation and prevent aneurysm development in a rat experimental model of AAA.
Aortic aneurysms were induced by implanting a segment of sodium dodecyl sulfate-decellularized guinea pig aorta in rat aortas. One day later, rats were randomized to AZD6140 (10 mg/kg twice daily by mouth) or diluent (n = 23 per group) for either 10 (n = 18) or 42 days (n = 28). Adenosine diphosphate (ADP)-mediated platelet aggregation, aneurysm expansion, intraluminal thrombus formation, inflammatory infiltration, matrix metalloproteinase-9 (MMP-9) expression, and smooth muscle cell colonization were measured.
AZD6140 inhibited ADP-induced platelet aggregation in vivo for 12 hours, justifying twice-daily administration in rats. The spontaneous increase in aortic diameter shown in the aneurysmal model (2.22 +/- 0.56 mm at day 10 vs 5.21 +/- 1.22 mm at day 42) was reduced with AZD6140 (3.61 +/- 1.46 mm at day 42, P < .01). This beneficial effect was associated with a significant reduction of thrombus development, platelet CD41 expression (P < .05), and leukocyte infiltration of the mural thrombus at days 10 and 42 (P < .01). MMP-9 expression correlated with mural thrombus area and was significantly reduced by AZD6140 (P < .05). AZD6140 limited elastic fiber degradation (P < .05) and enhanced progressive colonization of the thrombus by smooth muscle cells at day 42 (P < .01).
These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.
血小板活化和血栓更新是腹主动脉瘤（AAA）腔内血栓形成和进展的关键。本研究探讨了P2Y(12)受体拮抗剂AZD6140在大鼠AAA实验模型中抑制血小板活化和预防动脉瘤发展的能力。
通过将一段十二烷基硫酸钠脱细胞豚鼠主动脉植入大鼠主动脉来诱导主动脉瘤。一天后，将大鼠随机分为AZD6140组（口服10 mg/kg，每日两次）或稀释剂组（每组n = 23），持续10天（n = 18）或42天（n = 28）。测量二磷酸腺苷（ADP）介导的血小板聚集、动脉瘤扩张、腔内血栓形成、炎症浸润、基质金属蛋白酶-9（MMP-9）表达和平滑肌细胞定植情况。
AZD6140在体内抑制ADP诱导的血小板聚集达12小时，这证明在大鼠中每日给药两次是合理的。动脉瘤模型中显示的主动脉直径自发增加（第10天为2.22±0.56 mm vs第42天为5.21±1.22 mm）在使用AZD6140后有所减少（第42天为3.61±1.46 mm，P <.01）。这种有益效果与血栓形成的显著减少、血小板CD41表达（P <.05）以及在第10天和第42天壁血栓的白细胞浸润显著减少（P <.01）相关。MMP-9表达与壁血栓面积相关，并且被AZD6140显著降低（P <.05）。AZD6140限制了弹性纤维降解（P <.05），并在第42天增强了平滑肌细胞对血栓的渐进性定植（P <.01）。
这些数据表明，抑制血小板活化可限制腔内血栓的生物学活性，从而损害动脉瘤的发展。
