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


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.
Schultz
Geoffrey
G
Department of Vascular Surgery, Stanford University School of Medicine, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA.
Tedesco
Maureen M
MM
Sho
Eiketsu
E
Nishimura
Toshihiko
T
Sharif
Shadi
S
Du
Xiaoyan
X
Myles
Timothy
T
Morser
John
J
Dalman
Ronald L
RL
Leung
Lawrence L K
LL
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D001019:Aortic Rupture / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D025901:Carboxypeptidase B2 / Q000172:deficiency* / Q000235:genetics; D015936:Complement C5a / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005341:Fibrinolysin / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics; D010196:Pancreatic Elastase; D013997:Time Factors; D014148:Tranexamic Acid / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D001057:Apolipoproteins E; D018836:Inflammation Mediators; C506896:Spp1 protein, mouse; D053495:Osteopontin; D014148:Tranexamic Acid; D015936:Complement C5a; D025901:Carboxypeptidase B2; D010196:Pancreatic Elastase; D005341:Fibrinolysin