Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death.
Chiou
Shiun-Kwei
SK
Department of Veterans Affairs Medical Center, 5901 E. 7th St, Long Beach, CA 90822-5201, USA. skchiou@yahoo.com
Hodges
Amy
A
Hoa
Neil
N
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D015232:Dinoprostone / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000473:pathology*; D006801:Humans; D007213:Indomethacin / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D013467:Sulindac / Q000633:toxicity*; D015854:Up-Regulation; D000097642:GADD45 Proteins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016375:Antisense Elements (Genetics); D053453:Caspase 9; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D051545:Cyclooxygenase 1; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007213:Indomethacin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D013467:Sulindac; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins