title: 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.affiliation: *Nemours Biomedical Research and Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, U.S.A.
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.forename: Shaukat A
authors.initials: SA
authors.lastname: Khan
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsuda
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D006973:Hypertension / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; C084612:fibulin 2; D000804:Angiotensin II