| First Author | Johnston WF | Year | 2013 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 33 |
| Issue | 2 | Pages | 294-304 |
| PubMed ID | 23288154 | Mgi Jnum | J:216899 |
| Mgi Id | MGI:5609916 | Doi | 10.1161/ATVBAHA.112.300432 |
| Citation | Johnston WF, et al. (2013) Genetic and pharmacologic disruption of interleukin-1beta signaling inhibits experimental aortic aneurysm formation. Arterioscler Thromb Vasc Biol 33(2):294-304 |
| abstractText | OBJECTIVE: Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1beta (IL-1beta) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment. METHODS AND RESULTS: IL-1beta mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1beta (IL-1beta knockout [KO]) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0+/-5.5% for IL-1beta KO and 52.5+/-4.6% for IL-1R KO, compared with 89.4+/-4.0% for WT mice (P<0.005). Correspondingly, IL-1beta KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=-0.676; P<0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with control mice. CONCLUSIONS: IL-1beta is critical for AAA initiation and progression, and IL-1beta neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1beta signaling offers a novel pathway for AAA treatment. |
