Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death

Sandra Dunning

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Rebekka A. Hannivoort,

Rebekka A. Hannivoort

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Jan Freark De Boer,

Jan Freark De Boer

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Manon Buist-Homan,

Manon Buist-Homan

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Klaas Nico Faber,

Klaas Nico Faber

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Han Moshage,

Han Moshage

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Sandra Dunning,

Sandra Dunning

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Rebekka A. Hannivoort,

Rebekka A. Hannivoort

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Jan Freark De Boer,

Jan Freark De Boer

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Manon Buist-Homan,

Manon Buist-Homan

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Klaas Nico Faber,

Klaas Nico Faber

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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Han Moshage,

Han Moshage

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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First published: 05 June 2009

https://doi.org/10.1111/j.1478-3231.2009.02004.x

Citations: 28

Correspondence
Sandra Dunning, Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
Tel: +31 50 3619951
Fax: +31 50 3619306
e-mail: [email protected]

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Abstract

Background: In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described.

Aim: To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways.

Methods: Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5–25 μmol/L) or hydrogen peroxide (0.2–5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated.

Results: Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation.

Conclusion: Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status.

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Volume29, Issue6

July 2009

Pages 922-932

Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death

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Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death

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