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

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.

• Authors: Geoffrey Schultz, Maureen M Tedesco, Eiketsu Sho, Toshihiko Nishimura, Shadi Sharif, Xiaoyan Du, Timothy Myles, John Morser, Ronald L Dalman, Lawrence L K Leung
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 7 Pg. 1363-70 (Jul 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20431069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antifibrinolytic Agents
• Apolipoproteins E
• Inflammation Mediators
• Spp1 protein, mouse
• Osteopontin
• Tranexamic Acid
• Complement C5a
• Carboxypeptidase B2
• Pancreatic Elastase
• Fibrinolysin

Topics

• Animals
• Antifibrinolytic Agents (pharmacology)
• Aortic Aneurysm, Abdominal (chemically induced, enzymology, genetics, pathology, prevention & control)
• Aortic Rupture (chemically induced, enzymology, genetics, pathology, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Carboxypeptidase B2 (deficiency, genetics)
• Complement C5a (metabolism)
• Disease Models, Animal
• Disease Progression
• Fibrinolysin (metabolism)
• Inflammation Mediators (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteopontin (deficiency, genetics)
• Pancreatic Elastase
• Time Factors
• Tranexamic Acid (pharmacology)