AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2−/−), heterozygous (Fbln2+/−) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2−/− showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2−/− mice. The Fbln2+/− mice consistently displayed AngII-induced effects intermediate between WT and Fbln2−/−. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2−/− mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2−/− cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.
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Research Article|
October 14 2013
Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling
Hangxiang Zhang;
*Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
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Jing Wu;
*Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
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Hailong Dong;
Hailong Dong
*Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
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Shaukat A. Khan;
Shaukat A. Khan
*Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
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Mon-Li Chu;
Mon-Li Chu
†Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
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Takeshi Tsuda
*Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
Correspondence: Dr Takeshi Tsuda (email ttsuda@nemours.org).
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Publisher: Portland Press Ltd
Received:
November 28 2012
Revision Received:
July 08 2013
Accepted:
July 10 2013
Accepted Manuscript online:
July 10 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (4): 275–288.
Article history
Received:
November 28 2012
Revision Received:
July 08 2013
Accepted:
July 10 2013
Accepted Manuscript online:
July 10 2013
Citation
Hangxiang Zhang, Jing Wu, Hailong Dong, Shaukat A. Khan, Mon-Li Chu, Takeshi Tsuda; Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling. Clin Sci (Lond) 1 February 2014; 126 (4): 275–288. doi: https://doi.org/10.1042/CS20120636
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