Premium
Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death
Author(s) -
Dunning Sandra,
Hannivoort Rebekka A.,
De Boer Jan Freark,
BuistHoman Ma,
Faber Klaas Nico,
Moshage Han
Publication year - 2009
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2009.02004.x
Subject(s) - menadione , hepatic stellate cell , reactive oxygen species , superoxide , oxidative stress , programmed cell death , glutathione , hydrogen peroxide , microbiology and biotechnology , apoptosis , chemistry , biochemistry , biology , endocrinology , enzyme
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.