Abstract 17280: Metformin Inhibits Transforming Growth Factor-β1 And Cardiac Fibrosis by Targeting Hepatocyte Nuclear Factor 4α
Introduction: Metformin, a widely used antihyperglycaemic agent, is well-known as an adenosine monophosphate-activated protein kinase (AMPK) activator. Our previous study found that metformin inhibits pressure overload induced transforming growth factor-β1 (TGFβ1) production and cardiac fibrosis. However, the mechanisms underlying the inhibitory effect of metformin on TGFβ1 production are unknown. We used bioinformatics analysis to predict a potential hepatocyte nuclear factor 4α (HNF4α)-binding site in the promoter region of the Tgfb1 gene.
Hypothesis: We assessed the hypothesis that HNF4α is a novel transcriptional factor for Tgfb1 gene expression and a crucial regulator of cardiac fibrosis induced by AngII. We assessed the hypothesis that metformin inhibits HNF4α to decrease TGFβ1 production and subsequently attenuate cardiac fibrosis via AMPK activation.
Methods: Wild-type and AMPKα2-/- C57/BL6 mice were subcutaneously injected with metformin or saline and infused with AngII (3 mg/kg/day) for 7 days using a mini-pump. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments.
Results: Metformin inhibited AngII-induced cardiac fibrosis and TGFβ1 production in wild-type mice but not AMPKα2-/- mice. In CFs, metformin inhibited AngII-induced TGFβ1 expression via AMPK activation. AMPKα2 deficiency further increased AngII-induced cardiac TGFβ1 production in vivo. Overexpressing HNF4α increased TGFβ1 expression in CFs. HNF4α siRNA attenuated AngII-induced TGFβ1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4α protein expression and binding to the TGFβ1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4α protein levels in wild-type mice but not AMPKα2-/- mice.
Conclusions: HNF4α mediated AngII-induced TGFβ1 transcription and cardiac fibrosis. Metformin inhibited AngII-induced HNF4α expression via AMPK activation, thus decreasing TGFβ1 transcription and cardiac fibrosis. These findings reveal a novel cardioprotective mechanism of action of metformin and identify HNF4α as a new potential therapeutic target for cardiac fibrosis.
Author Disclosures: H. Xiao: None. R. Chen: None. Y. Feng: None. J. Wu: None. Y. Song: None. Y. Zhang: None.
- © 2016 by American Heart Association, Inc.