Abstract 1015: Knockout Of P27 Kip1 Accelerates Topical Elastase/3-aminopropionitrile Fumarate Salt-induced Abdominal Aortic Aneurysm Rupture In Mice

Abstract

Background: Abdominal aortic aneurysms (AAAs) are multifactorial diseases, and unknown genetic factors could contribute to aneurysms. The cell cycle inhibitor CDKN1B gene, also known as p27 Kip1 (p27), affects the arterial response to injury. Previous studies have shown that the loss of p27 exacerbates atherosclerosis progression by increasing vascular smooth muscle cells and macrophages. To assess the role of p27 in AAA development, another form of arterial response to inflammatory injury, we conducted experiments on the AAA model using p27 knockout (p27 -/- ) and wild-type (WT) mice. Methods: AAAs were induced in male and female p27 -/- and WT (C57BL/6J) mice by topically applying porcine pancreatic elastase and administrating 0.2% 3-aminopropionitrile fumarate salt (BAPN) in the drinking water. Topical elastase application was divided into active and heat-inactivated elastase groups. The aortic diameter was evaluated by ultrasound examination preoperatively and every 7 days postoperatively ( Fig. A ). Surviving mice were sacrificed after the final ultrasound evaluation, and aortic samples were collected for histological analysis. Results: Fig. B shows the aortic diameter change evaluated by ultrasound examination. AAA rupture occurred in one male p27-/- mice (33%, 1 of 3) and two female p27-/- mice (40%, 2 of 5), but in no WT mice of either gender. Macrophages were assessed using anti-F4/80 antibody. In the elastase-active group, both male and female p27 -/- mice had a significantly higher accumulation of macrophage than WT mice (P<0.01 and P<0.01, respectively), but there was no significant staining of F4/80 in the elastase-inactive group ( Fig. C and D ). Conclusions: Knockout of p27 exacerbated aneurysm rupture in a topical elastase/BAPN-induced AAA model and was associated with increased macrophage infiltration.