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Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1363-70. doi: 10.1161/ATVBAHA.109.202259. Epub 2010 Apr 29.

Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice.

Author information

1
Department of Vascular Surgery, Stanford University School of Medicine, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA.

Erratum in

  • Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):e165.

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.

PMID:
20431069
DOI:
10.1161/ATVBAHA.109.202259
[Indexed for MEDLINE]

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