Abstract 11059: Loss of Fibulin-2 Prevents Angiotensin (Ang) II-Induced Cardiac Fibrosis not only by Attenuating Transforming Growth Factor (TGF)-β but also by Up-Regulating Myocardial Natriuretic Peptides in the Mouse Model
Background: TGF-β and natriuretic peptides are known to functionally counteract each other during the development of cardiac remodeling. Recently we reported that loss of fibulin-2 protects against progressive ventricular remodeling by attenuating TGF-β activation in the mouse model. Here we studied how fibulin-2 modulates Ang II-induced cardiac fibrosis in relation to TGF-β and natriuretic peptides.
Methods: Pressor dosage of Ang II (2 μ g/kg/min) was continuously infused over 4 weeks by mini-Osmotic-pump in age-matched male fibulin-2 deficient (Fbln2-/-) and wild type (WT) mice. Sham mice received normal saline (n = 10 in each group).
Results: Ang II infusion induced the same degree of significant hypertension in both WT and Fbln2-/- mice. Echocardiogram revealed that equal degree of LV hypertrophy was induced by Ang II with no LV dilatation in both WT and Fbln2-/- mice (Table 1). Masson-Trichrome staining showed that Ang II-induced myocardial fibrosis in WT was markedly attenuated in Fbln2-/-. Ang II-induced increase in mRNA levels of TGF-β1, Collagen I, and Collagen III was significantly higher in WT than in Fbln2-/- mice. On the contrary, Ang II up-regulated ANP and BNP mRNA significantly higher in Fbln2-/- than in WT in the presence of equal degree of hypertrophy by Ang II. Ang II treatment significantly increased Smad2 activation in WT but not in Fbln2-/- mice, whereas it markedly increased ERK1/2 activation, downstream of BNP, in Fbln2-/- but not in WT mice.
Conclusions: Loss of fibulin-2 attenuated Ang II-induced cardiac fibrosis not only by suppressing TGF-β signaling pathways but also by up-regulating myocardial expression of ANP and BNP. Natriuretic peptides play an anti-fibrotic role by counteracting TGF-β. Our study suggested that fibulin-2 modulates an interaction between TGF-β and natriuretic peptides during the development of cardiac fibrosis via autocrine and paracrine fashion. .
- © 2012 by American Heart Association, Inc.