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Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

ABSTRACT: Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1?, or anti-IL-1? mAb blocked LCWE-induced AAA formation.Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1? and IL-1? play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

SUBMITTER: Wakita D

PROVIDER: S-EPMC4850105 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

Wakita Daiko D Kurashima Yosuke Y Crother Timothy R TR Noval Rivas Magali M Lee Youngho Y Chen Shuang S Fury Wen W Bai Yu Y Wagner Shawn S Li Debiao D Lehman Thomas T Fishbein Michael C MC Hoffman Hal M HM Shah Prediman K PK Shimada Kenichi K Arditi Moshe M

Arteriosclerosis, thrombosis, and vascular biology 20160303 5

<h4>Objective</h4>Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.<h4>Methods and results</h4>We discovered that in addition to aortitis, ...[more]

PMID: 26941015

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Project description:ObjectiveFew large-animal models exist for the study of aortic aneurysms. β-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease.MethodsInitial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28.ResultsSwine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine.ConclusionsBAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials.

Project description:ObjectiveCurrent management of small abdominal aortic aneurysms (AAAs) primarily involves serial imaging surveillance of maximum transverse diameter (MTD) to estimate rupture risk. Other measurements, such as volume and tortuosity, are less well-studied and may help characterize and predict AAA progression. This study evaluated predictors of AAA volume growth and discusses the role of volume in clinical practice.MethodsSubjects from the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (baseline AAA MTD, 3.5-5.0 cm) with ≥2 computed tomography scans were included in this study (n = 250). Computed tomography scans were conducted approximately every 6 months over 2 years. MTD, volume, and tortuosity were used to model growth. Univariable and multivariable backwards elimination least squares regressions assessed associations with volume growth.ResultsBaseline MTD accounted for 43% of baseline volume variance (P < .0001). Mean volume growth rate was 10.4 cm3/year (standard deviation, 8.8 cm3/year) (mean volume change +10.4%). Baseline volume accounted for 30% of volume growth variance; MTD accounted for 13% of volume growth variance. More tortuous aneurysms at baseline had significantly larger volume growth rates (difference, 32.8 cm3/year; P < .0001). Univariable analysis identified angiotensin II receptor blocker use (difference, -3.4 cm3/year; P = .02) and history of diabetes mellitus (difference, -2.8 cm3/year; P = .04) to be associated with lower rates of volume growth. Baseline volume, tortuosity index, current tobacco use, and absence of diabetes mellitus remained significantly associated with volume growth in multivariable analysis. AAAs that reached the MTD threshold for repair had a wide range of volumes: 102 cm3 to 142 cm3 in female patients (n = 5) and 105 cm3 to 229 cm3 in male patients (n = 20).ConclusionsBaseline AAA volume and MTD were found to be moderately correlated. On average, AAA volume grows about 10% annually. Baseline volume, tortuosity, MTD, current tobacco use, angiotensin II receptor blocker use, and history of diabetes mellitus were predictive of volume growth over time.

Project description:Background Development of abdominal aortic aneurysm (AAA) is associated with proinflammatory cytokines including interleukin-12 (IL12). Deficiency of interleukin 12p40 (IL12p40) increases localized fibrotic events by promoting TGFβ2 (transforming growth factor β)-dependent anti-inflammatory response. Here, we determined whether IL12p40 deficiency in apolipoprotein E-/- mice attenuates the development of AAA by antagonizing proinflammatory response. Methods and Results Double knockout (DKO) mice were generated by crossbreeding IL12p40-/- mice with apolipoprotein E-/- mice (n=12). Aneurysmal studies were performed using angiotensin II (1 µg/kg/min; subcutaneous). Surprisingly, DKO mice did not prevent the development of AAA with angiotensin II infusion. Immunohistological analysis, however, showed distinct pathological features between apolipoprotein E-/- and DKO mice. Polymerase chain reaction (7 day) and cytokine arrays (28 day) of the aortic tissues from DKO mice showed significantly increased expression of cytokines related to anti-inflammatory response (interleukin 5 and interleukin 13), synthetic vascular smooth muscle cell phenotype (Activin receptor-like kinase-1 (ALK-1), artemin, and betacellulin) and T helper 17-associated response (4-1BB, interleukin-17e (Il17e) and Cd40 ligand (Cd-40L)). Indeed, DKO mice exhibited increased expression of the fibro-proteolytic pathway in the medial layer of aortae induced by cellular communication network factor 2 (CCN2) and Cd3+IL17+ cells compared with apolipoprotein E-/- mice. Laser capture microdissection showed predominant expression of CCN2/TGFβ2 in the medial layer of human AAA. Finally, Ccn2 haploinsufficiency in the mice showed decreased AAA incidence in response to elastase infusion, associated with decreased matrix metalloproteinase-2 expression. Conclusions Our study reveals novel roles for IL12p40 deficiency in inducing fibro-proteolytic activities in the aneurysmal mouse model. Mechanistically, these effects of IL12p40 deficiency are mediated by CCN2/matrix metalloproteinase-2 crosstalk in the medial layer of aneurysmal aortae.

Dataset Information

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

Publications

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm.

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