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Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.
- Source :
-
Circulation [Circulation] 2014 Sep 09; Vol. 130 (11 Suppl 1), pp. S51-9. - Publication Year :
- 2014
-
Abstract
- Background: Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1β (IL-1β) is undetermined.<br />Methods and Results: IL-1β protein was measured in human TAAs and control aortas, and IL-1β protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6±24.7% compared with 14.4±8.2% for WT saline control (P<0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1β expression. Next, TAAs were induced in mice deficient of IL-1β (IL-1β knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1β and IL-1R significantly decreased thoracic aortic dilation (IL-1β knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1β knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1β and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2±15.5% versus anakinra: 68.3±19.2%; P<0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1±18.6% versus anakinra treatment: 59.7±25.7%; P=0.01).<br />Conclusions: Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1β decreased TAA formation and progression, indicating that IL-1β may be a potential target for TAA treatment.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Aged
Animals
Aortic Aneurysm, Thoracic chemically induced
Aortic Aneurysm, Thoracic drug therapy
Aortic Aneurysm, Thoracic pathology
Caspase 1 physiology
Comorbidity
Disease Models, Animal
Disease Progression
Drug Evaluation, Preclinical
Female
Humans
Interleukin 1 Receptor Antagonist Protein pharmacology
Interleukin-1beta deficiency
Interleukin-1beta genetics
Macrophages pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Muscle, Smooth, Vascular pathology
Pancreatic Elastase toxicity
Receptors, Interleukin-1 antagonists & inhibitors
Receptors, Interleukin-1 deficiency
Receptors, Interleukin-1 genetics
Thoracotomy
Aortic Aneurysm, Thoracic prevention & control
Interleukin 1 Receptor Antagonist Protein therapeutic use
Interleukin-1beta antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 130
- Issue :
- 11 Suppl 1
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 25200056
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.113.006800