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Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases.
J Hepatol. 2006 May; 44(5):918-29.JH

Abstract

BACKGROUND/AIMS

In liver diseases, reactive oxygen species (ROS) are involved in cell death and liver injury, but the mechanisms are not completely elucidated. To elucidate the mechanisms of hepatocyte cell death induced by the ROS superoxide anions and hydrogen peroxide, primary cultures of hepatocytes were exposed to the superoxide anion donor menadione (10-50 micromol/L) or H2O2 (1-5 mmol/L). Hepatocytes were also treated with caspases and MAPKs inhibitors, superoxide dismutase (PEG-SOD) and SNAP, a nitric oxide donor. Apoptosis was determined by measuring caspase-9, -6, -3 activation and cleaved PARP, and necrotic cell death by Sytox Green staining.

RESULTS

(1) Menadione (50 micromol/L) induces JNK phosphorylation, caspase-9, -6, -3 activation, PARP cleavage and apoptosis. Superoxide anions-induced apoptosis is dependent on JNK activity. Menadione (50 micromol/L) induces the phosphorylation of ERK1/2 and this attenuates cell death. (2) H2O2 increases necrotic cell death at high concentration or when H2O2 detoxification is impaired. H2O2 does not activate MAPKs signalling. (3) PEG-SOD prevents ERK1/2-, JNK- phosphorylation, caspase activation and apoptosis induced by menadione. Glutathione depletion increases menadione-induced apoptosis. (4) SNAP abolishes menadione-induced apoptosis but increases necrotic cell death.

CONCLUSIONS

In normal hepatocytes, superoxide anions-induced caspase activation and apoptosis is dependent on JNK activity and totally abolished by superoxide scavengers.

Authors+Show Affiliations

Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen, P.O. 30.001, 9700 RB, The Netherlands.No affiliation info availableNo 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

16310883

Citation

Conde de la Rosa, Laura, et al. "Superoxide Anions and Hydrogen Peroxide Induce Hepatocyte Death By Different Mechanisms: Involvement of JNK and ERK MAP Kinases." Journal of Hepatology, vol. 44, no. 5, 2006, pp. 918-29.
Conde de la Rosa L, Schoemaker MH, Vrenken TE, et al. Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. J Hepatol. 2006;44(5):918-29.
Conde de la Rosa, L., Schoemaker, M. H., Vrenken, T. E., Buist-Homan, M., Havinga, R., Jansen, P. L., & Moshage, H. (2006). Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. Journal of Hepatology, 44(5), 918-29.
Conde de la Rosa L, et al. Superoxide Anions and Hydrogen Peroxide Induce Hepatocyte Death By Different Mechanisms: Involvement of JNK and ERK MAP Kinases. J Hepatol. 2006;44(5):918-29. PubMed PMID: 16310883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. AU - Conde de la Rosa,Laura, AU - Schoemaker,Marieke H, AU - Vrenken,Titia E, AU - Buist-Homan,Manon, AU - Havinga,Rick, AU - Jansen,Peter L M, AU - Moshage,Han, Y1 - 2005/09/12/ PY - 2005/02/17/received PY - 2005/07/08/revised PY - 2005/07/21/accepted PY - 2005/11/29/pubmed PY - 2006/9/28/medline PY - 2005/11/29/entrez SP - 918 EP - 29 JF - Journal of hepatology JO - J Hepatol VL - 44 IS - 5 N2 - BACKGROUND/AIMS: In liver diseases, reactive oxygen species (ROS) are involved in cell death and liver injury, but the mechanisms are not completely elucidated. To elucidate the mechanisms of hepatocyte cell death induced by the ROS superoxide anions and hydrogen peroxide, primary cultures of hepatocytes were exposed to the superoxide anion donor menadione (10-50 micromol/L) or H2O2 (1-5 mmol/L). Hepatocytes were also treated with caspases and MAPKs inhibitors, superoxide dismutase (PEG-SOD) and SNAP, a nitric oxide donor. Apoptosis was determined by measuring caspase-9, -6, -3 activation and cleaved PARP, and necrotic cell death by Sytox Green staining. RESULTS: (1) Menadione (50 micromol/L) induces JNK phosphorylation, caspase-9, -6, -3 activation, PARP cleavage and apoptosis. Superoxide anions-induced apoptosis is dependent on JNK activity. Menadione (50 micromol/L) induces the phosphorylation of ERK1/2 and this attenuates cell death. (2) H2O2 increases necrotic cell death at high concentration or when H2O2 detoxification is impaired. H2O2 does not activate MAPKs signalling. (3) PEG-SOD prevents ERK1/2-, JNK- phosphorylation, caspase activation and apoptosis induced by menadione. Glutathione depletion increases menadione-induced apoptosis. (4) SNAP abolishes menadione-induced apoptosis but increases necrotic cell death. CONCLUSIONS: In normal hepatocytes, superoxide anions-induced caspase activation and apoptosis is dependent on JNK activity and totally abolished by superoxide scavengers. SN - 0168-8278 UR - https://www.unboundmedicine.com/medline/citation/16310883/Superoxide_anions_and_hydrogen_peroxide_induce_hepatocyte_death_by_different_mechanisms:_involvement_of_JNK_and_ERK_MAP_kinases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(05)00525-8 DB - PRIME DP - Unbound Medicine ER -