Nitric oxide suppresses transforming growth factor-β1-induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes

Xinchao Pan, Xunde Wang, Weiwei Lei, Lihua Min, Yanan Yang, Xin Wang, Jianguo Song

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Nitric oxide (NO) is a multifunctional regulator that is implicated in various physiological and pathological processes. Here we report that administration of NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited transforming growth factor-β1 (TGF-β1)-induced epithelial-to- mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Overexpression of inducible NO synthase (iNOS) by transfection of the iNOS-expressing vector, which increased NO production, also inhibited the TGF-β1-induced EMT and apoptosis in these cells. Treatment of cells with proinflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ, which increased the endogenous NO production, produced the same inhibitory effect. Furthermore, exogenous NO donor SNAP treatment caused a decrease in the intracellular adenosine triphosphate (ATP) levels. Consistently, depletion of intracellular ATP by mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited the TGF-β1-induced EMT and apoptosis, suggesting that an NO-induced decrease of ATP involved in the NO-mediated inhibition of TGF-β1-induced EMT and apoptosis. NO and FCCP also inhibited TGF-β1-induced STAT3 activation, suggesting that signal transducer and activator of transcription 3 inactivation is involved in the NO-induced effects on TGF-β1-induced EMT and apoptosis. Conclusion: Our study indicates that NO plays an important role in the inhibition of TGF-β1-induced EMT and apoptosis in mouse hepatocytes through the downregulation of intracellular ATP levels. The data provide an insight into the in vivo mechanisms on the function of NO during the processes of both EMT and apoptosis.

Original languageEnglish (US)
Pages (from-to)1577-1587
Number of pages11
JournalHepatology
Volume50
Issue number5
DOIs
StatePublished - Dec 1 2009

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Epithelial-Mesenchymal Transition
Transforming Growth Factors
Hepatocytes
Nitric Oxide
Apoptosis
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Adenosine Triphosphate
S-Nitroso-N-Acetylpenicillamine
Nitric Oxide Donors
Physiological Phenomena
STAT3 Transcription Factor
Nitric Oxide Synthase Type II
Pathologic Processes
Interleukin-1
Nitric Oxide Synthase
Interferons
Transfection
Down-Regulation
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Hepatology

Cite this

Nitric oxide suppresses transforming growth factor-β1-induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes. / Pan, Xinchao; Wang, Xunde; Lei, Weiwei; Min, Lihua; Yang, Yanan; Wang, Xin; Song, Jianguo.

In: Hepatology, Vol. 50, No. 5, 01.12.2009, p. 1577-1587.

Research output: Contribution to journalArticle

Pan, Xinchao ; Wang, Xunde ; Lei, Weiwei ; Min, Lihua ; Yang, Yanan ; Wang, Xin ; Song, Jianguo. / Nitric oxide suppresses transforming growth factor-β1-induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes. In: Hepatology. 2009 ; Vol. 50, No. 5. pp. 1577-1587.
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AU - Yang, Yanan

AU - Wang, Xin

AU - Song, Jianguo

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AB - Nitric oxide (NO) is a multifunctional regulator that is implicated in various physiological and pathological processes. Here we report that administration of NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited transforming growth factor-β1 (TGF-β1)-induced epithelial-to- mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Overexpression of inducible NO synthase (iNOS) by transfection of the iNOS-expressing vector, which increased NO production, also inhibited the TGF-β1-induced EMT and apoptosis in these cells. Treatment of cells with proinflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ, which increased the endogenous NO production, produced the same inhibitory effect. Furthermore, exogenous NO donor SNAP treatment caused a decrease in the intracellular adenosine triphosphate (ATP) levels. Consistently, depletion of intracellular ATP by mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited the TGF-β1-induced EMT and apoptosis, suggesting that an NO-induced decrease of ATP involved in the NO-mediated inhibition of TGF-β1-induced EMT and apoptosis. NO and FCCP also inhibited TGF-β1-induced STAT3 activation, suggesting that signal transducer and activator of transcription 3 inactivation is involved in the NO-induced effects on TGF-β1-induced EMT and apoptosis. Conclusion: Our study indicates that NO plays an important role in the inhibition of TGF-β1-induced EMT and apoptosis in mouse hepatocytes through the downregulation of intracellular ATP levels. The data provide an insight into the in vivo mechanisms on the function of NO during the processes of both EMT and apoptosis.

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