Enhanced Abdominal Aortic Aneurysm Formation in Thrombin-Activatable Procarboxypeptidase B–Deficient Mice Academic Article uri icon

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abstract

  • Objective— To determine whether procarboxypeptidase B (pCPB) −/− mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. Methods and Results— Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN]). Apolipoprotein E −/− OPN −/− mice are protected from experimental AAA formation. Murine AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion. Increased mortality secondary to AAA rupture was observed in pCPB −/− mice at the standard PPE dose. At reduced doses of PPE, pCPB −/− mice developed larger AAAs than wild-type controls (1.01±0.27 versus 0.68±0.05 mm; P =0.02 [mean±SD]). C5 −/− and OPN −/− mice were not protected against AAA development. Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in pCPB −/− mice. Conclusion— This study establishes the role of CPB in experimental AAA disease, indicating that CPB has a broad anti-inflammatory role in vivo. Enhanced AAA formation in the PPE model is the result of increased plasmin generation, not unregulated C5a- or OPN-mediated mural inflammation.

authors

  • Schultz, Geoffrey
  • Tedesco, Maureen M
  • Sho, Eiketsu
  • Nishimura, Toshihiko
  • Sharif, Shadi
  • Du, Xiaoyan
  • Myles, Timothy
  • Morser, John
  • Dalman, Ronald L
  • Leung, Laurence

publication date

  • July 2010

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