Abstract 14034: Follistatin-like 1 Protein Attenuates Cardiac Hypertrophy Following Pressure Overload.
Background: Transforming growth factor (TGF)-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 1 (Fstl1) is expressed in the normal adult heart and is induced in response to conditions that promote myocardial hypertrophy and heart failure. Fstl1 has an anti-proliferative effect but its function in the heart is largely unknown. The aim of this study was to investigate the role of Fstl1 in cardiac hypertrophy. Here we identified Fstl1 as a novel secreted anti-hypertrophic regulatory factor in the heart.
Methods and Results: To elucidate the loss of Fstl1 function in the heart, we generated cardiaomyocyte specific Fstl1 knock-out (CKO) mice and investigated Fstl1-CKO mice and their wild-type (WT) littermates, which were subjected to pressure overload caused by transverse aortic constriction (TAC). Fstl1-CKO mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Fstl1-CKO mice also demonstrated a pronounced loss in ventricular performance following 4 weeks of pressure overload stimulation compared to WT controls and this is accompanied by reduced AMPK activity. In addition, administration of Fstl1 in Fstl1-CKO mice cancelled this loss of ventricular functions following pressure overload. Conversely, to elucidate the gain of Fstl1 function, we generated transgenic mice with muscle specific over-expression and examined these Fstl1 transgenic (TG) mice following TAC compared with their WT littermates. Fstl1-TG mice were resistant to pressure overload-induced hypertrophy. Administration of Fstl1 promoted activation of AMPK and antagonized phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes. Inhibition of AMPK attenuated an anti-hypertrophic effect by Fstl1 treatment, whereas block of LKB1 attenuated AMPK phosphorylation.
Conclusions: These results identify Fstl1 as a novel autocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving AMPK axis.
- © 2010 by American Heart Association, Inc.