Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-ß signalling.
Clin Sci (Lond)
; 126(4): 275-88, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-23841699
ABSTRACT
AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-ß serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-ß 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-ß 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-ß1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-ß-downstream signalling markers, Smad2, TAK1 (TGF-ß-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-ß-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-ß activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-ß-mediated cardiac hypertrophy via enhanced TGF-ß activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Vasoconstritores
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Proteínas de Ligação ao Cálcio
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Angiotensina II
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Transdução de Sinais
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Proteínas da Matriz Extracelular
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Fator de Crescimento Transformador beta
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Cardiomegalia
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Hipertensão
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article