Abstract 334: Enhanced Abdominal Aortic Aneurysm Formation in Procarboxypeptidase B-Deficient Mice
Objective: Osteopontin (OPN)-deficient mice are protected from experimental abdominal aortic aneurysm (AAA) formation. Thrombin cleavage of OPN enhances its inflammatory property; thrombin bound to endothelial thrombomodulin activates procarboxypeptidase B (proCPB), which inactivates thrombin-cleaved OPN. We hypothesize that proCPB knockout (CPB KO) mice will develop larger AAAs due to increased vascular inflammation from unregulated thrombin-cleaved OPN.
Methods: AAAs in wild-type (WT) and CPB KO mice were created with intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were sacrificed at postoperative days 3, 7, and 14. Average AAA diameters were calculated by histometry of the aortic tisse samples.
Results: CPB KO mice underwent perfusion with 15u/mL PPE (9 mice) and 10u/ml PPE (7 mice). Mortality within 72 hours due to AAA rupture was 66% and 43%, respectively. At 7.5u/mL PPE, none of the CPB KO mice expired due to AAA rupture. Histometry data from 22 CPB KO mice and 24 WT mice [PPE at 7.5 u/mL and normal saline (NS) controls] were compared at postoperative days 3, 7, and 14 (see Table⇓). At postoperative days 3 and 7, the average lumen and outer diameters of the CPB KO + PPE mice AAAs were significantly greater than the WT + PPE AAA diameters (62% and 48.6% lumen diameter increase respectively). At postoperative day 14, the CPB KO + PPE mice demonstrated decreased AAA diameters compared to day 7 (32% decrease, p>0.05).
Conclusion: The high AAA rupture rates in the CPB KO mice with high PPE doses and the markedly increased AAA size at the lower PPE dose at days 3 and 7 suggests that proCPB provides a vasoprotective, anti-inflammatory effect on AAA development. The reason for the apparent decrease in AAA diameter at day 14 in the CPB KO mice is unclear. Thrombin may mediate AAA progression via activation of thrombin-cleaved OPN. Whether the pro CPB protective effect in AAA formation is mediated by its inhibition of thrombin-cleaved OPN is under investigation.