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Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.

ABSTRACT: We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall.Using an elastase-induced model of AAA, we showed that pretreatment of C57BL/6 mice with cobra venom factor, which depleted serum of complement activity, protected mice from AAA development. Whereas control mice exhibited a mean aortic diameter of 156+/-2% on day 14 after elastase perfusion, mice treated with cobra venom factor exhibited a mean aortic diameter of 90+/-4% (P<0.001). Examination of mice deficient in factor B further indicated that the alternative pathway of complement played a major role in this process (mean aortic diameter of 105+/-4% in factor B-deficient mice, P<0.001 compared with controls). Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, which recruited neutrophils to the aortic wall. Moreover, antagonism of both C3a and C5a activity was required to block AAA, which suggests that each can independently promote the aneurysmal phenotype. In addition, we demonstrated that complement alternative-pathway involvement was not restricted to this experimental model but was also evident in human AAAs.The identification of involvement of the complement system in the pathophysiology of AAA provides a new target for therapeutic intervention in this common disease.

SUBMITTER: Pagano MB

PROVIDER: S-EPMC2758616 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.

Pagano Monica B MB Zhou Hui-fang HF Ennis Terri L TL Wu Xiaobo X Lambris John D JD Atkinson John P JP Thompson Robert W RW Hourcade Dennis E DE Pham Christine T N CT

Circulation 20090323 13

<h4>Background</h4>We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall.<h4>Methods and results</h4>Using an elastase-induced model of AA ...[more]

PMID: 19307471

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Project description:ObjectiveMurine models have proved instrumental in studying various aspects of abdominal aortic aneurysm (AAA), from identification of underlying pathophysiologic changes to the development of novel therapeutic strategies. In the current study, we describe a new model in which an elastase-treated donor aorta is transplanted to a recipient mouse and allowed to progress to aneurysm. We hypothesized that by transplanting an elastase-treated abdominal aorta of one genotype to a recipient mouse of a different genotype, one can differentiate pathophysiologic factors that are intrinsic to the aortic wall from those stemming from circulation and other organs.MethodsElastase-treated aorta was transplanted to the infrarenal abdominal aorta of recipient mice by end-to-side microsurgical anastomosis. Heat-inactivated elastase-treated aorta was used as a control. Syngeneic transplants were performed with use of 12-week-old C57BL/6 littermates. Transplant grafts were harvested from recipient mice on day 7 or day 14 after surgery. The aneurysm outcome was measured by aortic expansion, elastin degradation, proinflammatory cytokine expression, and inflammatory cell infiltration and compared with that produced with the established, conventional elastase infusion model.ResultsThe surgical technique success rate was 75.6%, and the 14-day survival rate was 51.1%. By day 14 after surgery, all of the elastase-treated transplanted abdominal aortas had dilated and progressed to AAAs, defined as 100% or more increase in the maximal external diameter compared with that measured before elastase perfusion, whereas none of the transplanted aortas pretreated with inactive elastase became aneurysmal (percentage increase in maximum aortic diameter: 159.36% ± 23.27%, transplanted elastase, vs 41.46% ± 9.34%, transplanted inactive elastase). Aneurysm parameters, including elastin degradation and infiltration of macrophages and T lymphocytes, were found to be identical to those observed in the conventional elastase model. Quantitative polymerase chain reaction analysis revealed similarly increased levels of proinflammatory cytokines (relative changes of mRNA in the conventional elastase model vs transplant model: tumor necrosis factor α, 1.71 ± 0.27 vs 2.93 ± 0.86; monocyte chemoattractant protein 1, 2.36 ± 0.58 vs 2.87 ± 0.51; chemokine (C-C motif) ligand 5, 3.37 ± 0.92 vs 3.46 ± 0.83; and interferon γ, 3.09 ± 0.83 vs 5.30 ± 1.69). Using green fluorescent protein transgenic mice as donors or recipients, we demonstrated that a small quantity of mononuclear leukocytes in the transplant grafts bared the genotype of the donors.ConclusionsTransplanted elastase-treated abdominal aorta could develop to aneurysm in recipient mice. This AAA transplant model can be used to examine how the microenvironment of a transplanted aneurysmal aorta may be altered by the contributions of the "global" environment of the recipient.

Project description:BACKGROUND:Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. METHODS:We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. RESULTS:Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1? as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1? and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1? via recruiting the transcription factor specificity protein 1 to the promoter region. CONCLUSIONS:The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Dataset Information

Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.

Publications

Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.

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