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Metformin attenuates angiotensin II-induced TGF?1 expression by targeting hepatocyte nuclear factor-4-?.

ABSTRACT: BACKGROUND AND PURPOSE:Metformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGF?1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGF?1 production induced by angiotensin II (AngII) and the underlying mechanisms. EXPERIMENTAL APPROACH:Wild-type and AMPK?2-/- C57BL/6 mice were injected s.c. with metformin or saline and infused with AngII (3 mg·kg-1 ·day-1 ) for 7 days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments. KEY RESULTS:In CFs, metformin inhibited AngII-induced TGF?1 expression via AMPK activation. Analysis using bioinformatics predicted a potential hepatocyte nuclear factor 4? (HNF4?)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4? increased TGF?1 expression in CFs. HNF4? siRNA attenuated AngII-induced TGF?1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4? protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4? protein levels in wild-type mice but not in AMPK?2-/- mice. Consequently, metformin inhibited AngII-induced TGF?1 production and cardiac fibrosis in wild-type mice but not in AMPK?2-/- mice. CONCLUSIONS AND IMPLICATIONS:HNF4? mediates AngII-induced TGF?1 transcription and cardiac fibrosis. Metformin inhibits AngII-induced HNF4? expression via AMPK activation, thus decreasing TGF?1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4? as a new potential therapeutic target for cardiac fibrosis. LINKED ARTICLES:This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

SUBMITTER: Chen R

PROVIDER: S-EPMC5867023 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Metformin attenuates angiotensin II-induced TGFβ1 expression by targeting hepatocyte nuclear factor-4-α.

Chen Ruifei R Feng Yenan Y Wu Jimin J Song Yao Y Li Hao H Shen Qiang Q Li Dan D Zhang Jianshu J Lu Zhizhen Z Xiao Han H Zhang Youyi Y

British journal of pharmacology 20170324 8

<h4>Background and purpose</h4>Metformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGFβ1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGFβ1 production induced by angiotensin II (AngII) and the underlying mechanisms.<h4>Experimental approach</h4>Wild-type and AMPKα2<sup>-/-</sup> C57BL/6 mic ...[more]

PMID: 28230250

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Project description:Fibrosis is an ominous pathological process in failing myocardium, but its pathogenesis is poorly understood. We recently reported that loss of an extracellular matrix (ECM) protein, fibulin-2, protected against ventricular dysfunction after myocardial infarction (MI) in association with absence of activation of transforming growth factor (TGF)-β signaling and suppressed upregulation of ECM protein expression during myocardial remodeling. Here we investigated the role of fibulin-2 in the development of myocardial hypertrophy and fibrosis induced by continuous pressor-dosage of angiotensin II (Ang II) infusion. Both wild type (WT) and fibulin-2 null (Fbln2KO) mice developed comparable hypertension and myocardial hypertrophy by Ang II infusion. However, myocardial fibrosis with significant upregulation of collagen type I and III mRNA was only seen in WT but not in Fbln2KO mice.Transforming growth factor (TGF)-β1 mRNA and its downstream signal, Smad2, were significantly upregulated in WT by Ang II, whereas there were no Ang II-induced changes in Flbn2KO, suggesting fibulin-2 is necessary for Ang II-induced TGF-β signaling that induces myocardial fibrosis. To test whether fibulin-2 is sufficient for Ang II-induced TGF-β upregulation, isolated Flbn2KO cardiac fibroblasts were treated with Ang II after transfecting with fibulin-2 expression vector or pretreating with recombinant fibulin-2 protein. Ang II-induced TGF-β signaling in Fbln2KO cells was partially rescued by exogenous fibulin-2, suggesting that fibulin-2 is required and probably sufficient for Ang II-induced TGF-β activation. Smad2 phosphorylation was induced just by adding recombinant fibulin-2 to KO cells, suggesting that extracellular interaction between fibulin-2 and latent TGF-β triggered initial TGF-β activation. Our study indicates that Ang II cannot induce TGF-β activation without fibulin-2 and that fibulin-2 has an essential role in Ang II-induced TGF-β signaling and subsequent myocardial fibrosis. Fibulin-2 can be considered as a critical regulator of TGF-β that induces myocardial fibrosis.

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Metformin attenuates angiotensin II-induced TGF?1 expression by targeting hepatocyte nuclear factor-4-?.

Publications

Metformin attenuates angiotensin II-induced TGFβ1 expression by targeting hepatocyte nuclear factor-4-α.

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