Thioredoxin-1 attenuates indomethacin-induced gastric mucosal injury in mice.
Indomethacin is one of non-steroidal anti-inflammatory drugs that are commonly used clinically and often cause gastric mucosal injury as a side effect. Generation of reactive oxygen species (ROS) and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric mucosal injury. Thioredoxin-1 (Trx-1) is a small redox-active protein with anti-oxidative activity and redox-regulating functions. The aim of this study was to investigate the protective effect of Trx-1 against indomethacin-induced gastric mucosal injury. Trx-1 transgenic mice displayed less gastric mucosal damage than wild type (WT) C57BL/6 mice after intraperitoneal administration of indomethacin. Administration of recombinant human Trx-1 (rhTrx-1) or transfection of the Trx-1 gene reduced indomethacin-induced cytotoxicity in rat gastric epithelial RGM-1 cells. Pretreatment with rhTrx-1 suppressed indomethacininduced ROS production and downregulation of phosphorylated Akt in RGM-1 cells. Survivin, a member of inhibitors of apoptosis proteins family, was downregulated by indomethacin, which was suppressed in Trx-1 transgenic mice or by administration of rhTrx-1 in RGM-1 cells. Trx-1 inhibits indomethacin-induced apoptotic signaling and gastric ulcer formation, suggesting that it may have a preventive and therapeutic potential against indomethacin-induced gastric injury.
Tan
Aiguo
A
Department of Biological Responses, Kyoto University, Institute for Virus Research, Sakyo, Kyoto, Japan.
Nakamura
Hajime
H
Kondo
Norihiko
N
Tanito
Masaki
M
Kwon
Yong-Won
YW
Ahsan
M Kaimul
MK
Matsui
Hirofumi
H
Narita
Makiko
M
Yodoi
Junji
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C515559:Txn1 protein, mouse; D013879:Thioredoxins; D007213:Indomethacin