Abstract 481: Pharmacological Inhibition of Calpain Attenuates Mineralocorticoid Receptor Agonist and High Salt-Induced Abdominal Aortic Aneurysm Incidence and Aortic Rupture in Mice

Abstract

Background and Objective: Recently, we demonstrated that pharmacological and genetic inhibition of calpains, a class of calcium-activated neutral cysteine proteases, attenuated angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) in mice. A newly identified non-invasive model of aneurysm has been developed in mice using deoxycorticosterone acetate (DOCA) coated pellets and oral administration of high salt. It is interesting to note that in this model, systemic administration of renin angiotensin inhibitors had no effect on aneurysm formation. The purpose of this study was to test whether pharmacological inhibition of calpain would influence AAA formation induced by mineralocorticoid receptor agonism and high salt in mice. Methods and Results: To determine whether calpain inhibition influenced DOCA and high salt-induced AAAs, 9 month old male C57BL/6 mice were administered calpain inhibitor, BDA-410 (30 mg/kg/day) or vehicle (n=10 per group) by oral gavage 1 week before DOCA pellet implantation and throughout the subsequent 21 days. Mice were implanted with DOCA pellets (50mg/ mouse for 21 days) and maintained on high salt (0.9% NaCl and 0.2% KCl) water. Calpain inhibition significantly suppressed AAA incidence (defined as increase in aortic diameter or AAA rupture; Vehicle = 60% vs BDA = 20%; P<0.05) compared to the vehicle group. Calpain inhibition also significantly protected DOCA + high salt-induced aortic rupture (Vehicle = 6/10 vs BDA = 1/10; P<0.05) in mice. Conclusion: These data demonstrate that calpain activation plays a critical role in not only AngII-induced, but also aldosterone pathways accelerated AAA formation in mice.