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

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 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.

Prevention of UVB Radiation-induced Epidermal Damage by Expression of Heat Shock Protein 70

“…Interestingly, GGA, a leading anti-ulcer drug on the Japanese market, has been reported to be an HSP inducer, up-regulating various HSPs not only in cultured gastric mucosal cells but also in various tissues in vivo (41). It was reported that GGA suppresses not only gastric lesions but also lesions of the small intestine, inflammatory bowel disease-related experimental colitis, and neurodegenerative diseases (39,40,46,47). On the other hand, the use of HSP70 inducers in cosmetics -1) (B).…”

Present status and strategy of NSAIDs-induced small bowel injury

“…A PPI was administered 30 min before indomethacin administration: omeprazole (30, 100 mg/kg), lansoprazole (30, 100 mg/kg), or rabeprazole (30, 100 mg/kg). The following were administered twice-30 min before and 6 h after indomethacin administration: an H 2 receptor antagonist (famotidine (3, 10 mg/kg), cimetidine (100 mg/kg), lafutidine [50] (30 mg/kg), or roxatidine [51] (60, 100, 200 mg/kg)); a mucosal protective agent (teprenone [52] (100, 300 mg/kg), rebamipide [53] (100, 300 mg/kg), irsogladine [54] (1, 10 mg/kg), ecabet sodium [55] (300 mg/kg)); sucralfate (500 mg/kg) or a PG analog (misoprostol (0.1 mg/kg)).…”

Suppression of Melanin Production by Expression of HSP70

“…Because stressor-induced tissue damage is involved in various diseases, HSPs and HSP inducers have received much attention for their therapeutic potential. For example, we have shown using transgenic mice that HSP70 protects the gastrointestinal tract from development of gastric and small intestinal lesions and inflammatory bowel disease (17)(18)(19)(20). Interestingly, geranylgeranylacetone, a leading anti-ulcer drug on the Japanese market, has been reported to be a nontoxic HSP-inducer, up-regulating various HSPs not only in cultured gastric mucosal cells but also in various tissues, including the gastric mucosa in vivo (21).…”