Abstract 3467: Fibulin-2 Enhances Angiotensin-II-Induced Transforming Growth Factor (TGF)-β Activation in Promoting Cardiac Remodeling in the Mouse Model I n Vivo

Abstract

Background: Angiotensin-II (Ang-II) is a potent neurohormone responsible for progression of cardiac remodeling in which TGF-β serves as a principal downstream mediator. In our previous study, genetic deletion of fibulin-2 attenuated progression of ventricular dysfunction after experimental myocardial infarction (MI). Because Ang-II plays a central role in post-MI ventricular remodeling, we tested the hypothesis that fibulin-2 modulates Ang-II-induced cardiac remodeling. Methods: Subpressor dosage of Ang-II (0.2 μg/kg/min) was infused over 4 weeks by mini-osmotic-pump in age matched wild-type (WT), heterozygous, and fibulin-2 null (Fbln2 −/− ) adult male mice. Sham mice received normal saline. Results: There was no blood pressure change throughout Ang-II treatment. WT developed significant left ventricular (LV) hypertrophy by Ang-II, whereas Ang-II-treated Fbln2 −/− mice showed no noticeable hypertrophy compared with sham: LV/body weight ratio (WT 4.83±0.18 vs. Fbln2 −/− 4.01± 0.12 mg/g, p < 0.05) and LV posterior wall thickness by echocardiogram (WT 0.76± 0.03 vs. Fbln2 −/− 0.71± 0.02 mm, p < 0.05). Atrial natriuretic peptide (ANP) mRNA expression was significantly increased in Ang-II-treated WT compared with sham, but not in Ang-II-treated Flbn2 −/− . Ang-II also induced significant up-regulation in fibulin-2, Collagen I, Collagen III, and MMP-2 mRNA level in WT, but not in Fbln2 −/− . Both TGF-β1 mRNA and protein expression were significantly up-regulated in Ang-II-treated WT, but were unchanged in Ang-II-treated Fbln2 −/− compared with sham. Activation of TGF-β downstream signaling proteins, phosphorylated forms of Smad2, TGF-β-activated kinase 1 (TAK1), and p38MAPK, were all significantly increased in Ang-II-treated WT, as opposed to no increase in Ang-II-treated Fbln2 −/− compared with sham. Heterozygous mice showed intermediate increase in LV hypertrophy, matrix protein synthesis, and activation of TGF-β downstream signaling pathways between WT and Fbln2 −/− . Conclusions: Our data suggest that fibulin-2 enhances Ang-II-induced myocardial hypertrophy via up-regulation of TGF-β and its downstream signaling pathways in dose-dependent fashion and that fibulin-2 is required for Ang-II-induced TGF-β activation. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).