Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs

Mayuko Aburaya, Ken Ichiro Tanaka, Tatsuya Hoshino, Shinji Tsutsumi, Keitarou Suzuki, Masaki Makise, Reiko Akagi, Tohru Mizushima

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74 Citations (Scopus)

Abstract

Gastric mucosal cell death by non-steroidal anti-inflammatory drugs (NSAIDs) is suggested to be involved in NSAID-induced gastric lesions. Therefore, cellular factors that suppress this cell death are important for protection of the gastric mucosa from NSAIDs. Heme oxygenase-1 (HO-1) is up-regulated by various stressors and protects cells against stressors. Here, we have examined up-regulation of HO-1 by NSAIDs and the contribution of HO-1 to the protection of gastric mucosal cells against NSAIDs both in vitro and in vivo. In cultured gastric mucosal cells, all NSAIDs tested up-regulated HO-1. In rats, orally administered indomethacin up-regulated HO-1, induced apoptosis, and produced lesions at gastric mucosa. An inhibitor of HO-stimulated NSAID-induced apoptosis in vitro and in vivo and also stimulated NSAID-produced gastric lesions, suggesting that NSAID-induced up-regulation of HO-1 protects the gastric mucosa from NSAID-induced gastric lesions by inhibiting NSAID-induced apoptosis. Indomethacin activated the HO-1 promoter and caused nuclear accumulation of NF-E2-related factor 2 (Nrf2), a transcription factor for the HO-1 gene. Examination of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and experiments with its inhibitor strongly suggest that the nuclear accumulation of Nrf2 and resulting upregulation of HO-1 by NSAIDs is mediated through NSAID-dependent activation (phosphorylation) of p38 MAPK. This is the first report showing the protective role of HO-1 against irritant-induced gastric lesions.

Original languageEnglish
Pages (from-to)33422-33432
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number44
DOIs
Publication statusPublished - 2006 Nov 3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Aburaya, M., Tanaka, K. I., Hoshino, T., Tsutsumi, S., Suzuki, K., Makise, M., Akagi, R., & Mizushima, T. (2006). Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs. Journal of Biological Chemistry, 281(44), 33422-33432. https://doi.org/10.1074/jbc.M602074200