Document Detail

A role for HSP70 in protecting against indomethacin-induced gastric lesions.
MedLine Citation:
PMID:  19439408     Owner:  NLM     Status:  MEDLINE    
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 E(2) 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 reticulum stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSF1-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.
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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-13     Completed Date:  2009-09-25     Revised Date:  2010-09-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19705-15     Citation Subset:  IM    
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
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MeSH Terms
Anti-Inflammatory Agents, Non-Steroidal / toxicity
Apoptosis / drug effects*
Cell Line, Tumor
DNA-Binding Proteins / genetics,  metabolism
Dinoprostone / metabolism
Diterpenes / pharmacology
Flow Cytometry
Gastric Mucosa / drug effects,  metabolism,  pathology
HSP70 Heat-Shock Proteins / genetics,  metabolism*,  physiology
In Situ Nick-End Labeling
Indomethacin / toxicity*
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Mice, Transgenic
RNA, Small Interfering / genetics
Reverse Transcriptase Polymerase Chain Reaction
Stomach Ulcer / chemically induced,  metabolism*,  physiopathology
Transcription Factors / genetics,  metabolism
bcl-2-Associated X Protein / metabolism
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/DNA-Binding Proteins; 0/Diterpenes; 0/HSP70 Heat-Shock Proteins; 0/Hsf1 protein, mouse; 0/RNA, Small Interfering; 0/Transcription Factors; 0/bcl-2-Associated X Protein; 363-24-6/Dinoprostone; 53-86-1/Indomethacin; 6809-52-5/geranylgeranylacetone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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