Abstract 522: Enhanced Abdominal Aortic Aneurysm (AAA) Formation in Procarboxypeptidase B (pCPB)-Deficient Mice
Objective: pCPB is activated by thrombin to CPB and inhibits plasmin generation and other pro-inflammatory mediators including osteopontin (OPN). We hypothesize that CPB KO mice will develop larger AAAs due to unregulated OPN.
Methods: AAAs in mice were created via intra-aortic elastase (PPE) infusion. AAA diameters were determined by ultrasonography or histometry. AAA tissues were also used for determination of matrix metalloproteinase (MMP) levels.
Results: CPB KO mice (n = 8) demonstrated increased mortality due to AAA rupture at standard doses of PPE (66%) compared to WT mice (n = 5, 0%). At reduced doses of PPE, CPB KO mice developed larger AAAs compared to WT mice (1.01±0.27mm vs 0.68±0.05 mm, p = 0.004). OPN KO mice did not show protection against AAA development at reduced or standard doses of PPE (n = 8, 0.70±0.17mm, 0.77±0.05 mm, respectively), indicating that OPN does not play a significant role in this AAA model. We then hypothesized that CPB KO mice will have enhanced plasmin generation, resulting in increased MMP activation and larger AAAs. WT mice were treated with tranexamic acid (TXA, 15 mg subq daily), which blocked plasmin generation as demonstrated by prolonged clot lysis time ex vivo. TXA (drug) treatment completely reversed the enhanced AAA formation in the CPB KO (n = 6) as compared to WT (n= 5) mice (Figure 1⇓). MMP-2 and 9 levels in AAA tissues were suppressed by TXA (Figure 2⇓).
Conclusion: CPB KO mice develop larger AAAs, confirming the role of CPB in experimental AAAs. The enhanced AAA formation is due to increased plasmin generation and MMP activation, rather than through the OPN pathway. Serum levels of CPB may be a useful marker of clinical AAA disease and/or progression.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).