Induction and intracellular localization of a 72-kDa heat shock protein in rat gastric mucosa after water-immersion stress

Zeniya, Akira; Otaka, Michiro; Kuwabara, Toshiyuki; Fujimori, Shusei; Otani, Setsuya; Tashima, Yohtalou; Masamune, Osamu

doi:10.1007/bf02367781

Cited by 35 publications

(29 citation statements)

References 30 publications

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“…A number of previous observations have suggested that HSPs, especially HSP70, play an important role in protecting gastric mucosa against the development of lesions (17,18,(33)(34)(35)(36)(37)(38)(39). However, prior to the current study, little direct evidence, genetic or otherwise, existed to support this idea.…”

Section: Discussionmentioning

confidence: 62%

A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions

Suemasu

Tanaka

Namba

et al. 2009

Journal of Biological Chemistry

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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 upregulated 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.

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Section: Discussionmentioning

confidence: 62%

A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions

Suemasu

Tanaka

Namba

et al. 2009

Journal of Biological Chemistry

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“…It showed that 400 probes, including 5 genes associated with HSP70 and the heat-shock transcription factor-1 gene, were up-regulated at least 1.5-fold after a 6-hour exposure to indomethacin (500 µ M ) in comparison with the vehicle-treated cells. In the gastric mucosa, the cytoprotective ability of HSP70 in vivo and in vitro has been reported [15,16,17,18]. On the other hand, Jin et al [19 ]reported that the pre-induction of HSP did not have a cytoprotective function in small-intestinal damage caused by indomethacin.…”

Section: Discussionmentioning

confidence: 98%

Heat-Shock Protein 70-Overexpressing Gastric Epithelial Cells Are Resistant to Indomethacin-Induced Apoptosis

et al. 2009

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Background/Aims: Protecting intestinal mucosa from nonsteroidal anti-inflammatory drugs is still an unsolved problem. It has been revealed that apoptosis in epithelial cells as a result of mitochondrial injury is an important pathogenesis in indomethacin-induced gastric mucosal injury. In this study, we revealed the effect of overexpressed heat-shock protein 70 (HSP70) in indomethacin-induced apoptosis and oxidative stress. Methods: HSP70-overexpressing rat gastric mucosal cells (7018-RGM-1 cells) and control cells (pBK-CMV-12 cells) were used and treated with 0–500 μM of indomethacin for 24 h. Cell viability and cytotoxity were measured by a WST-8 assay and a lactate dehydrogenase release assay, respectively. Apoptosis was observed by fluorescence microscopy staining with Hoechst 33342 and propidium iodide. The expression of Bcl-2 family proteins, activation of caspase-3, and 4-hydroxy-2-nonenal (4-HNE)-modified proteins were assessed by Western blot analysis. Results: Indomethacin caused apoptosis of gastric epithelial cells. The 7018-RGM-1 cells survived significantly after indomethacin treatment compared to the control cells. The increase in pro-apoptotic Bad proteins, the decrease in anti-apoptotic Bcl-2 proteins, and caspase activation were all suppressed in the 7018-RGM-1 cells. A lower level of indomethacin-induced 4-HNE-modification was detected in the 7018-RGM-1 cells than in the control cells. Conclusion: Overexpressed HSP70 may potentiate resistance to apoptosis and oxidative stress in indomethacin-induced gastric epithelial cell injury.

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“…Artificial up-regulation of HSPs, especially HSP70, by GGA (a clinically used antiulcer drug) or other methods in cultured gastric mucosal cells confers protection from irritant-induced cell death (Nakamura et al, 1991;Hirakawa et al, 1996;Mizushima et al, 1999;Tomisato et al, 2000Tomisato et al, , 2001Takano et al, 2002), whereas exposure to such irritants induces HSP production (Zeniya et al, 1995;Otani et al, 1997;Itoh and Noguchi, 2000;Saika et al, 2000). In this study, we found that HSF1-null mice are more susceptible to irritant-induced gastric lesions, providing direct genetic evidence for the significance of HSPs in ameliorating the outcome of irritant-induced gastric insults.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported not only that various gastric irritants, including ethanol, up-regulate HSPs, but also that artificial up-regulation of HSPs confers resistance to these irritants in cultured gastric mucosal cells (Nakamura et al, 1991;Hirakawa et al, 1996;Mizushima et al, 1999;Saika et al, 2000;Tomisato et al, 2000Tomisato et al, , 2001. Similar up-regulation of HSPs by gastric irritants has also been recorded in vivo, in addition to which whole-body heat treatment has been shown to suppress gastric irritant-induced lesions (Zeniya et al, 1995;Otani et al, 1997;Itoh and Noguchi, 2000;Saika et al, 2000). Although these findings strongly indicate that HSPs are protective, very little direct evidence exists, and to date, no in vivo study has been conducted to demonstrate that inhibition of HSPs results in a phenotype susceptible to irritant-induced gastric lesions.…”

mentioning

confidence: 82%

Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions

Tanaka

Tsutsumi²,

Arai³

et al. 2006

Mol Pharmacol

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Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes. The severity of gastric lesions induced by ethanol or hydrochloric acid was worsened in HSF1-null mice. Immunoblotting, real-time reverse transcription-polymerase chain reaction, immunohistochemical analysis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed that the ethanol administration up-regulated gastric mucosal HSPs, in particular HSP70, in an HSF1-dependent manner, and more apoptotic cells were observed in the gastric mucosa of HSF1-null mice than in wild-type mice. In contrast, other parameters governing the gastric ulcerogenic response, including gastric acid secretion, gastric mucosal blood flow, and prostaglandin E 2 levels, were not significantly affected by the absence of the hsf1 gene. Geranylgeranylacetone (GGA), a clinically used antiulcer drug with HSP-inducing activity, suppressed ethanol-induced gastric lesions in wild-type mice but not in heat shock factor 1 (HSF1)-null mice. The results suggest that the aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate HSPs, leading to apoptosis. It is also suggested that the HSP-inducing activity of GGA contributes to the drug's antiulcer activity. This study provides direct genetic evidence that HSPs, after their HSF1-dependent up-regulation, confer gastric protection against the irritant-induced lesions.The balance between aggressive and defensive factors determines development of gastric lesions, with either a relative increase in aggressive insults or a relative decrease in protective factors, resulting in lesions. The gastric mucosa is challenged by a variety of both endogenous and exogenous irritants (aggressive factors), including ethanol, gastric acid, pepsin, reactive oxygen species, nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori. These irritants damage the mucosal cells, inducing cell death, which leads to the formation of gastric lesions (Holzer, 1998). To protect the gastric mucosa, a complex defense system, which includes the production of surface mucus and bicarbonate and the regulation of gastric mucosal blood flow (GMBF), has evolved. Prostaglandins (PGs), in particular PGE 2 , enhance these protective mechanisms and are therefore believed to comprise a major gastric mucosal defensive factor (Miller, 1983).Heat shock proteins (HSPs) have also attracted considerable attention as another major defensive factor. When cells are exposed to stressors, a number of so-called stress proteins are induced to confer protection against such stressors. HSPs

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Induction and intracellular localization of a 72-kDa heat shock protein in rat gastric mucosa after water-immersion stress

Cited by 35 publications

References 30 publications

A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions

A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions

Heat-Shock Protein 70-Overexpressing Gastric Epithelial Cells Are Resistant to Indomethacin-Induced Apoptosis

Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions

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