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 experimental model of AAA.


METHODS
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.
Dai
Jianping
J
INSERM U698, Cardiovascular Haematology, Bio-Engineering and Remodeling, Bichat-Claude Bernard Hospital, Paris, France.
Louedec
Liliane
L
Philippe
Monique
M
Michel
Jean-Baptiste
JB
Houard
Xavier
X
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004547:Elastic Tissue / Q000187:drug effects / Q000473:pathology; D006168:Guinea Pigs; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D011917:Rats, Inbred Lew; D018048:Receptors, Purinergic P2 / Q000097:blood; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000077486:Ticagrelor; D013997:Time Factors; D014183:Transplantation, Heterologous
C553058:P2ry12 protein, rat; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D020780:Matrix Metalloproteinase 9; D000077486:Ticagrelor; D000241:Adenosine