| First Author | Zhang H | Year | 2014 |
| Journal | Clin Sci (Lond) | Volume | 126 |
| Issue | 4 | Pages | 275-88 |
| PubMed ID | 23841699 | Mgi Jnum | J:315283 |
| Mgi Id | MGI:6829998 | Doi | 10.1042/CS20120636 |
| Citation | Zhang H, et al. (2014) Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-beta signalling. Clin Sci (Lond) 126(4):275-88 |
| abstractText | AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-beta serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-beta 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-beta 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 mug/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-beta1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-beta-downstream signalling markers, Smad2, TAK1 (TGF-beta-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-beta-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-beta activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-beta-mediated cardiac hypertrophy via enhanced TGF-beta activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling. |
