Essential role of p38 MAPK in caspase-independent, iPLA2-dependent cell death under hypoxia/low glucose conditions

Aoto, Mamoru; Shinzawa, Koei; Suzuki, Yoji; Ohkubo, Nobutaka; Mitsuda, Noriaki; Tsujimoto, Yoshihide

doi:10.1016/j.febslet.2009.04.028

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Volume 583, Issue 10 , Pages 1611-1618, 19 May 2009

Essential role of p38 MAPK in caspase-independent, iPLA₂-dependent cell death under hypoxia/low glucose conditions

Edited by Vladimir Skulachev

Mamoru Aoto
- Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan
- Corresponding authors. Address: Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, Osaka 565-0871, Japan (Y. Tsujimoto). Fax: +81 89 960 5246 (M. Aoto), +81 6 6879 3369 (Y. Tsujimoto).
Koei Shinzawa
- Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, Osaka 565-0871, Japan
- Solution Oriented Research for Science and Technology (SORST) of the Japan Science and Technology Agency (JST), Osaka, Japan
Yoji Suzuki
- Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan
Nobutaka Ohkubo
- Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan
Noriaki Mitsuda
- Department of Physiology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan
Yoshihide Tsujimoto
- Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, Osaka 565-0871, Japan
- Solution Oriented Research for Science and Technology (SORST) of the Japan Science and Technology Agency (JST), Osaka, Japan
- Corresponding authors. Address: Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, Osaka 565-0871, Japan (Y. Tsujimoto). Fax: +81 89 960 5246 (M. Aoto), +81 6 6879 3369 (Y. Tsujimoto).

Received 16 March 2009; received in revised form 16 April 2009; accepted 16 April 2009. published online 23 April 2009.

Abstract

The mechanisms of cell death induced by hypoxia or ischemia are not yet fully understood. We have previously demonstrated that cell death induced by hypoxia occurs independently of caspases, and is mediated by phospholipase A₂ (PLA₂).

Here, we show that p38 mitogen-activated protein kinase is activated under hypoxia. A selective inhibitor of p38 or decrease in the p38alpha protein level prevents hypoxia-induced cell death. The p38 inhibitor abolishes PLA₂ activation by hypoxia, indicating that p38 acts upstream of PLA₂. The antioxidant N-acetyl-cysteine inhibits activation of p38 and cell death induced by hypoxia, indicating that reactive oxygen species (ROS) are responsible for p38 activation. These results demonstrate that the ROS/p38/PLA₂ signaling axis has a crucial role in caspase-independent cell death induced by hypoxia.

Abbreviations: AA, arachidonic acid, ATF-2, activating transcription factor-2, BEL, bromoenol lactone, cPLA₂, calcium-dependent PLA₂, iPLA₂, calcium-independent PLA₂, MAPK, mitogen-activated protein kinase, LDH, lactate dehydrogenase, NAC, N-acetyl-cysteine, PED6, N-((6-(2,4-dinitrophenyl)amino)hexanoyl)-2-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-sn-glycero-3-phosphoethanolamine, PLA₂, phospholipase A₂, ROS, reactive oxygen species, siRNA, small interfering RNA, TPA, 12-O-tetradecanoylphorbol 13-acetate