Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model

Background 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 exp...

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Veröffentlicht in:Journal of vascular surgery 2009-03, Vol.49 (3), p.719-727
Hauptverfasser: Dai, Jianping, MD, PhD, Louedec, Liliane, BSc, Philippe, Monique, BSc, Michel, Jean-Baptiste, MD, PhD, Houard, Xavier, PhD
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Sprache:eng
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Zusammenfassung:Background 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. Method 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. Results 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). Conclusions These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.
ISSN:0741-5214
1097-6809
DOI:10.1016/j.jvs.2008.09.057