scholarly journals A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

2015 ◽  
Vol 35 (2) ◽  
pp. 389-398 ◽  
Author(s):  
Smriti M. Krishna ◽  
Sai Wang Seto ◽  
Roby J. Jose ◽  
Erik Biros ◽  
Corey S. Moran ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Apolipoprotein E ◽  
Deficient Mouse ◽  
Abdominal Aortic ◽  
Thrombospondin 1 ◽  
Peptide Antagonist

scholarly journals Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysm

BMC Genomics ◽  
2009 ◽  
Vol 10 (1) ◽  
pp. 298 ◽  
Author(s):  
Catherine Rush ◽  
Moses Nyara ◽  
Joseph V Moxon ◽  
Alexandra Trollope ◽  
Bradford Cullen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Apolipoprotein E ◽  
Whole Genome ◽  
Deficient Mouse ◽  
Genome Expression ◽  
Abdominal Aortic ◽  
Whole Genome Expression

scholarly journals High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice

2017 ◽  
Vol 131 (12) ◽  
pp. 1261-1281 ◽  
Author(s):  
Smriti Murali Krishna ◽  
Sai Wang Seto ◽  
Roby Jose ◽  
Jiaze Li ◽  
Joseph Moxon ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Ex Vivo ◽  
High Serum ◽  
Matricellular Protein ◽  
Body Tissues ◽  
Age Related ◽  
Abdominal Aortic ◽  
Thrombospondin 1

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman’s rho −0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19–0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1−/−ApoE−/−, n=20) and control mice (ApoE−/−, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1−/− ApoE−/− mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1−/−ApoE−/− mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1−/−ApoE−/− mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1−/−ApoE−/− mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.

scholarly journals UCP-2 is involved in angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0179743 ◽  
Author(s):  
Peng Yan ◽  
Ken Chen ◽  
Qiang Wang ◽  
Dachun Yang ◽  
De Li ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Apolipoprotein E ◽  
Knockout Mice ◽  
Abdominal Aortic ◽  
Apolipoprotein E Knockout Mice

scholarly journals Interleukin 12p40 Deficiency Promotes Abdominal Aortic Aneurysm by Activating CCN2/MMP2 Pathways

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Neekun Sharma ◽  
Chetan P. Hans
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Inflammatory Response ◽  
Matrix Metalloproteinase ◽  
Apolipoprotein E ◽  
Matrix Metalloproteinase 2 ◽  
Cell Phenotype ◽  
Abdominal Aortic ◽  
Anti Inflammatory

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.

Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth

2019 ◽  
Vol 133 (21) ◽  
pp. 2203-2215 ◽  
Author(s):  
Smriti M. Krishna ◽  
Corey S. Moran ◽  
Roby J. Jose ◽  
Sharon Lazzaroni ◽  
Pacific Huynh ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Apolipoprotein E ◽  
Vehicle Control ◽  
Cell Depletion ◽  
Matrix Degradation ◽  
Abdominal Aortic

Abstract Objective: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE–/–) mouse model. Approach: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140–386, and enhanced green fluorescent protein (eGFP)-ApoE–/– (CD11c.DOG.ApoE–/–) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study. Results: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P<0.001). CD11c+ depletion commencing after AAA establishment by 14 days of AngII infusion, was also shown to lead to smaller AAAs than controls after a further 14 days (D.tox, 1.54 ± 0.04 mm vs Vehicle control, 1.80 ± 0.03 mm, P<0.001). Flow cytometry revealed significantly lower numbers of circulating CD44hi CD62Llo effector CD4 T cells, CD44hi CD62Llo effector CD8 T cells and B220+ B cells in CD11c+ cell-depleted mice versus controls. CD11c+ depletion attenuated SRA matrix degradation indicated by decreased neutrophil elastase activity (P=0.014), lower elastin degradation score (P=0.012) and higher collagen content (P=0.002). Conclusion: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis.

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