Platelet Inhibitors Reduce Rupture in a Mouse Model of Established Abdominal Aortic Aneurysm

Abstract

Objective Rupture of abdominal aortic aneurysms (AAAs) causes a high morbidity and mortality in the elderly population. Platelet-rich thrombi form on the surface of aneurysms and may contribute to disease progression. In this study, we used a pharmacologic approach to examine a role of platelets in established aneurysms induced by angiotensin II (AngII) infusion into hypercholesterolemic mice. Approach and Results Administration of the platelet inhibitors aspirin (ASA) or clopidogrel bisulfate to established AAAs dramatically reduced rupture. The mechanism of protection appears to be a reduction in abdominal aortic platelet and macrophage recruitment resulting in decreased active matrix metalloproteinases (MMPs) 2 and 9. Platelet inhibitors also resulted in reduced plasma concentrations of platelet factor 4, cytokines, and components of plasminogen activation system in mice. To determine the validity of these findings in human subjects, eligible aneurysm patients were retrospectively analyzed using developed and validated algorithms in the electronic medical record database at Vanderbilt University. Similar to mice, administration of ASA or P2Y12 inhibitors was associated with reduced death amongst AAA patients. Conclusions These results suggest that platelets contribute to AAA progression and rupture.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…The accelerated accumulation of platelets at the lesion site provides hemostatic protection initially, but, as the lesion progresses, platelets via production of proinflammatory mediators like PDGF could contribute to aneurysm formation. 26,27 Although platelets are the main source of PDGF, other cell types, including VSMCs, endothelial cells, and inflammatory cells, also produce this agent. 28,32,46 Therefore, the contribution of CYP1B1 to the expression of the four different isoforms of PDGF was assessed at the site of the lesion in Ang IIeinduced AAA.…”

“…Since platelets also contribute to inflammation in AAA, 26 we determined the localization of CD62p þ -activated platelets in aortic sections from Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and from Apoe À/À / Cyp1b1 À/À mice. Ang II infusion for 28 days increased the accumulation of F4/80 þ macrophages, CD3 þ T cells, and CD62p þ -activated platelets at the lesion site in the aortae of Apoe À/À /Cyp1b1 þ/þ mice but not in mice concurrently receiving TMS or in Apoe À/À /Cyp1b1 À/À mice ( Figure 2).…”

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice

“…[25] Blood was collected from the inferior vena cava and plasma prepared as previously described. [11,26]…”

Aortic Aneurysms

“…58–60 To extend insights into the contributions of platelets to AAA, Owens and colleagues studied the effects of platelet inhibitors, aspirin and clopidogrel, on established AAA in AngII-infused mice and found that inhibition of platelets profoundly reduced aortic rupture. 61 In addition to effects of platelets in thrombosis and AAA, thrombomodulin, a cofactor of thrombin, has also been reported to contribute to both calcium chloride-induced and AngII-induced AAA in mice. 62 Findings in these study implicate important roles of hemostatic factors in the development and progression of AAA.…”