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Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death.
Liver Int. 2009 Jul; 29(6):922-32.LI

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 micromol/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.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. s.dunning@med.umcg.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19386027

Citation

Dunning, Sandra, et al. "Superoxide Anions and Hydrogen Peroxide Inhibit Proliferation of Activated Rat Stellate Cells and Induce Different Modes of Cell Death." Liver International : Official Journal of the International Association for the Study of the Liver, vol. 29, no. 6, 2009, pp. 922-32.
Dunning S, Hannivoort RA, de Boer JF, et al. Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. Liver Int. 2009;29(6):922-32.
Dunning, S., Hannivoort, R. A., de Boer, J. F., Buist-Homan, M., Faber, K. N., & Moshage, H. (2009). Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. Liver International : Official Journal of the International Association for the Study of the Liver, 29(6), 922-32. https://doi.org/10.1111/j.1478-3231.2009.02004.x
Dunning S, et al. Superoxide Anions and Hydrogen Peroxide Inhibit Proliferation of Activated Rat Stellate Cells and Induce Different Modes of Cell Death. Liver Int. 2009;29(6):922-32. PubMed PMID: 19386027.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. AU - Dunning,Sandra, AU - Hannivoort,Rebekka A, AU - de Boer,Jan Freark, AU - Buist-Homan,Manon, AU - Faber,Klaas Nico, AU - Moshage,Han, Y1 - 2009/04/06/ PY - 2009/4/24/entrez PY - 2009/4/24/pubmed PY - 2009/10/31/medline SP - 922 EP - 32 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int VL - 29 IS - 6 N2 - 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 micromol/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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/19386027/Superoxide_anions_and_hydrogen_peroxide_inhibit_proliferation_of_activated_rat_stellate_cells_and_induce_different_modes_of_cell_death_ L2 - https://doi.org/10.1111/j.1478-3231.2009.02004.x DB - PRIME DP - Unbound Medicine ER -