Abstract 9873: Inhibition of IL-1β Signaling Prevents Aneurysm Formation in a Novel Model of Thoracic Aortic Aneurysm
Objective: To determine the role of IL-1β signaling in a novel model of thoracic aortic aneurysms (TAAs).
Methods: To develop a TAA model, 8-10 week old male C57Bl/6 wild type mice (WT) underwent thoracotomy with topical placement of an elastase soaked sponge (WT elastase) or saline soaked sponge (WT saline) for 5.5 minutes. Mice recovered and aortic dilation was measured in vivo at 3, 7, 14, 21 and 28 days (n=5 each). Next, to determine the contribution of IL-1β signaling in TAA formation, TAAs were induced in mice deficient of IL-1β (IL-1β KO) or IL-1 receptor (IL-1R KO) (n=10 each). Maximal aortic dilation was measured and thoracic aortas were harvested for histology and protein analysis. Last, WT mice pre-treated with either IL-1R antagonist anakinra (100mg/kg/day) or vehicle alone (n=8 per group) underwent the elastase TAA model to determine effects of pharmacologic IL-1R antagonism.
Results: Application of an elastase soaked sponge to the thoracic aorta resulted in a progressive dilation over time with maximal aortic dilation of 99.6±24.7% at day 14 compared to 14.4±8.2% for WT saline control (p<0.0001). WT elastase aortas had increased elastin fragmentation, smooth muscle cell degradation, and infiltration by macrophages and neutrophils compared to saline aortas. Compared to positive WT controls, genetic deletion of IL-1β and IL-1R significantly decreased thoracic aortic dilation (WT control = 104.7±23.8% vs. IL-1β KO = 54.2±16.8% and IL-1R KO = 62.6±17.2%, p<0.05 for both). Both IL-1β KO and IL-1R KO aortas demonstrated preserved elastin and smooth muscle cell staining and decreased macrophage and neutrophil staining. Correspondingly, IL-1β and IL-1R KO aortas had significantly decreased inflammatory cytokines and MMP-9. Pretreatment of WT mice with anakinra inhibited TAA formation with reduction in maximal aortic dilation from 99.2±15.5% in the vehicle-treated mice to 73.3±24.9% in mice treated with anakinra (p<0.05).
Conclusions: Topical application of elastase to the thoracic aorta reproducibly produces aortic dilation with molecular and histologic features that are consistent with TAA disease. Both genetic and pharmacologic inhibition of IL-1β signaling prevent TAA formation and may be a potential therapeutic target in human disease.
- © 2013 by American Heart Association, Inc.