Abstract 194: Pharmacologic Inhibition By Spironolactone Attenuates Experimental Abdominal Aortic Aneurysms

Abstract

Introduction: Abdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant risk of mortality. Spironolactone has been recently described as a pannexin-1 (Panx1) channel modulator. Our hypothesis focuses on the role of spironolactone on Panx1 channels to attenuate AAA formation. Methods: A topical elastase (0.4 U/mL type 1 porcine pancreatic elastase) or heat inactivated elastase (control) AAA model was used in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone (1.25 mg/kg) i.p. daily for 14 days. On day 14, the abdominal aortic diameter was measured by video micrometry and expressed as percentage increase over baseline. In a second model, mice were subjected to β-aminopropionitrile (BAPN) two days prior to elastase treatment and everyday thereafter. A vehicle control (saline) or spironolactone was given i.p. daily starting from day 14. Immunohistochemistry was used to analyze immune cell infiltration and elastic fiber disruption (Verhoeff Van Gieson staining). Groups were compared using ANOVA and data is displayed as mean ± SEM with p<0.05 as statistically significant. Results: Aortic diameter was significantly increased in elastase-treated WT mice compared to controls (202.5 ± 4.2% vs 0.5 ± 1.9%; n=9/group, p<0.001). Elastase-treated WT mice administered spironolactone had a significant, dose-independent decrease in AAA formation compared to elastase-treated WT controls (139.8 ± 9.9% vs 202.5 ± 4.2%; n=10/group, p<0.001). Elastase-treated mice given BAPN and administered spironolactone had significant attenuation of AAA formation compared to controls on day 28 (420.2 ± 30.5% vs 643.8 ± 41.3%; n=8/group, p<0.001). A significant decrease in immune cell infiltration and elastic fiber disruption occurred in all mice treated with spironolactone compared to respective controls. Conclusion: These results suggest spironolactone mitigates aortic remodeling to attenuate AAA formation as well as decrease growth of preformed aneurysms. Further studies aim to characterize the molecular mechanisms of specific intercellular interactions involving Panx1-mediated AAA formation by spironolactone.