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Genetic and pharmacologic disruption of interleukin-1? signaling inhibits experimental aortic aneurysm formation.

ABSTRACT: Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1? (IL-1?) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment.IL-1? 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-1? (IL-1? 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-1? KO and 52.5±4.6% for IL-1R KO, compared with 89.4±4.0% for WT mice (P<0.005). Correspondingly, IL-1? 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.IL-1? is critical for AAA initiation and progression, and IL-1? neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1? signaling offers a novel pathway for AAA treatment.

SUBMITTER: Johnston WF

PROVIDER: S-EPMC3632435 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.

Johnston William F WF Salmon Morgan M Su Gang G Lu Guanyi G Stone Matthew L ML Zhao Yunge Y Owens Gary K GK Upchurch Gilbert R GR Ailawadi Gorav G

Arteriosclerosis, thrombosis, and vascular biology 20130103 2

<h4>Objective</h4>Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1β (IL-1β) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment.<h4>Methods and results</h4>IL-1β mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion ...[more]

PMID: 23288154

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Project description:BACKGROUND: Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. METHODS AND FINDINGS: Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE(2) stimulation increased EP4 protein expression (1.4 ± 0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4 ± 0.03- and 1.7 ± 0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE(-/-) mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4(+/-)/ApoE(-/-) mice exhibited significantly less AAA formation than EP4(+/+)/ApoE(-/-) mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl(2) application was also reduced in EP4(+/-) mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6 ± 0.06- and 0.7 ± 0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. CONCLUSION: An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.

Dataset Information

Genetic and pharmacologic disruption of interleukin-1? signaling inhibits experimental aortic aneurysm formation.

Publications

Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.

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