1. Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice.
- Author
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Schultz G, Tedesco MM, Sho E, Nishimura T, Sharif S, Du X, Myles T, Morser J, Dalman RL, and Leung LL
- Subjects
- Animals, Antifibrinolytic Agents pharmacology, Aortic Aneurysm, Abdominal chemically induced, Aortic Aneurysm, Abdominal genetics, Aortic Aneurysm, Abdominal pathology, Aortic Aneurysm, Abdominal prevention & control, Aortic Rupture chemically induced, Aortic Rupture genetics, Aortic Rupture pathology, Aortic Rupture prevention & control, Apolipoproteins E deficiency, Apolipoproteins E genetics, Carboxypeptidase B2 genetics, Complement C5a metabolism, Disease Models, Animal, Disease Progression, Fibrinolysin metabolism, Inflammation Mediators blood, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteopontin deficiency, Osteopontin genetics, Pancreatic Elastase, Time Factors, Tranexamic Acid pharmacology, Aortic Aneurysm, Abdominal enzymology, Aortic Rupture enzymology, Carboxypeptidase B2 deficiency
- 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., Conclusions: 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.
- Published
- 2010
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