A role for HSP70 in protecting against indomethacin-induced gastric lesions

Shintaro Suemasu, Ken Ichiro Tanaka, Takushi Namba, Tomoaki Ishihara, Takashi Katsu, Mitsuaki Fujimoto, Hiroaki Adachi, Gen Sobue, Koji Takeuchi, Akira Nakai, Tohru Mizushima

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72 Citations (Scopus)

Abstract

A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, is gastrointestinal complications.. Both NSAID-dependent cyclooxygenase inhibition and gastric mucosal apoptosis are involved in NSAID-produced gastric lesions, and this apoptosis is mediated by the endoplasmic reticulum stress response and resulting activation of Bax. Heat shock-proteins (HSPs) have been suggested to protect gastric mucosa from NSAID-induced lesions; here we have tested this idea genetically. The severity of gastric lesions produced by indomethacin was worse in mice lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes, than in control mice. Indomethacin administration up-regulated the expression of gastric mucosal HSP70. Indomethacin-induced gastric lesions were ameliorated in transgenic mice expressing HSP70. After indomethacin administration, fewer apoptotic cells were observed in the gastric mucosa of transgenic mice expressing HSP70 than in wild-type mice, whereas the gastric levels of prostaglandin E2 for the two were indistinguishable. This suggests that expression of HSP70 ameliorates indomethacin-induced gastric lesions by affecting mucosal apoptosis. Suppression of HSP70 expression in vitro stimulated indomethacin-induced apoptosis and activation of Bax but not the endoplasmic reticulitm stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSFI-dependent manner and suppressed the formation of indomethacin-induced gastric lesions in wild-type mice but not in HSF1-null mice. The results of this study provide direct genetic evidence that expression of HSP70 confers gastric protection against indomethacin-induced lesions by inhibiting the activation of Bax. The HSP inducing activity of geranylgeranylacetone seems to contribute to its gastroprotective activity against indomethacin.

Original languageEnglish
Pages (from-to)19705-19715
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number29
DOIs
Publication statusPublished - 2009 Jul 17

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Suemasu, S., Tanaka, K. I., Namba, T., Ishihara, T., Katsu, T., Fujimoto, M., Adachi, H., Sobue, G., Takeuchi, K., Nakai, A., & Mizushima, T. (2009). A role for HSP70 in protecting against indomethacin-induced gastric lesions. Journal of Biological Chemistry, 284(29), 19705-19715. https://doi.org/10.1074/jbc.M109.006817