Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling.

Abstract

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.

• Authors: Hangxiang Zhang, Jing Wu, Hailong Dong, Shaukat A Khan, Mon-Li Chu, Takeshi Tsuda
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 126 Issue 4 Pg. 275-88 (Feb 2014) ISSN: 1470-8736 [Electronic] England
• PMID: 23841699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Extracellular Matrix Proteins
• Transforming Growth Factor beta
• Vasoconstrictor Agents
• fibulin 2
• Angiotensin II

Topics

• Angiotensin II (pharmacology)
• Animals
• Calcium-Binding Proteins (deficiency, metabolism)
• Cardiomegaly (genetics, metabolism, pathology)
• Extracellular Matrix Proteins (deficiency, metabolism)
• Fibrosis (metabolism)
• Hypertension (etiology, genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (etiology, genetics)
• Myocardium (pathology)
• Signal Transduction
• Transforming Growth Factor beta (genetics, metabolism)
• Vasoconstrictor Agents (pharmacology)