GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency
Ping Ye, Wenhao Chen, Jie Wu, Xiaofan Huang, Jun Li, Sihua Wang, Zheng Liu, Guohua Wang, Xiao Yang, Peng Zhang, Qiulun Lv, Jiahong Xia
Ping Ye, Wenhao Chen, Jie Wu, Xiaofan Huang, Jun Li, Sihua Wang, Zheng Liu, Guohua Wang, Xiao Yang, Peng Zhang, Qiulun Lv, Jiahong Xia
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Research Article Cardiology

GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

Abstract

Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3–/– mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4+ T cells from Smad3–/– mice also induced aortitis in Smad3+/+ recipient mice, while depletion of CD4+ T cells in Smad3–/– mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3+/– mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3–/– CD4+ T cells secreted more GM-CSF than Smad3+/+ CD4+ T cells. GM-CSF induced CD11b+Gr-1+Ly-6Chi inflammatory monocyte accumulation in the aortic root, but administration of anti–GM-CSF mAb to Smad3–/– mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.

Authors

Ping Ye, Wenhao Chen, Jie Wu, Xiaofan Huang, Jun Li, Sihua Wang, Zheng Liu, Guohua Wang, Xiao Yang, Peng Zhang, Qiulun Lv, Jiahong Xia

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Figure 11

SMAD3 mutations in a family with AOS and the aorta tissue from 1 case showed inflammatory infiltration and increased GM-CSF expression.

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SMAD3 mutations in a family with AOS and the aorta tissue from 1 case sh...
(A) Pedigrees with SMAD3 mutations. Squares, males; circles, females. Filled symbols indicate individuals with thoracic aortic aneurysm and/or dissection. Symbols represent individuals with a normal or unknown phenotype. (B) The sequence chromatogram of SMAD3 shows a heterozygous mutation. (C) Secondary structures of SMAD3, which are described by Jpred3 ( http://www.compbio.dundee.ac.uk/www-jpred/). The mutation (p.Thr329Ala) is located in β-folding near H2, which is in the MHI domain of SMAD3. (D) Cross-species protein conservation of SMAD3 around the mutation (p.Thr329Ala) which is described by the IBIVU Server ( http://www.ibi.vu.nl/programs/pralinewww/). (E) H&E staining and immunohistochemistry staining of transverse sections of aorta from a control (donor) and a patient with SMAD3 mutation. It showed inflammatory infiltration and increased GM-CSF expression in the aorta tissues from case 2. Original magnification, ×100 (top panels); ×400 (middle and bottom panels).