Rebamipide, a gastro-protective drug, inhibits indomethacin-induced apoptosis in cultured rat gastric mucosal cells: association with the inhibition of growth arrest and DNA damage-induced 45 alpha expression.
Rebamipide, a gastromucosal protective drug, suppresses indomethacin-induced gastropathy in humans and rodents. Effects of rebamipide on gene expression in indomethacin-treated gastric mucosal cells (RGM1) were investigated using high-density oligonucleotide arrays. Indomethacin induced apoptosis in RGM1 cells in a dose-dependent manner. Rebamipide pretreatment significantly reduced indomethacin-induced apoptosis. We used gene expression profiling on high-density oligonucleotide probe arrays to characterize the transcriptional response of RGM1 cells to indomethacin treatment for 6 hr. Of the 8,799 probes examined, 717 (8.1%) were induced (400 probes) or repressed (317 probes) at least 1.5-fold. Among the 158 genes that were induced by indomethacin at least 2.0-fold, four genes that were down-regulated by rebamipide at least 2.0-fold are listed: growth arrest and DNA-damage-inducible 45 alpha (GADD 45 alpha), golgi SNAP receptor complex member 1, iodothyronine deiodinases, and transcription factor 8. Real time-PCR confirmed GADD 45 alpha expression and its inhibition by rebamipide. Inhibition of apoptosis-related genes is possibly important for the cytoprotective effect of rebamipide against indomethacin-induced gastric mucosal cell injury.
Naito
Yuji
Y
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. ynaito@koto.kpu-m.ac.jp
Kajikawa
Hirokazu
H
Mizushima
Katsura
K
Shimozawa
Makoto
M
Kuroda
Masaaki
M
Katada
Kazuhiro
K
Takagi
Tomohisa
T
Handa
Osamu
O
Kokura
Satoshi
S
Ichikawa
Hiroshi
H
Yoshida
Norimasa
N
Matsui
Hirofumi
H
Yoshikawa
Toshikazu
T
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology*; D020869:Gene Expression Profiling; D007213:Indomethacin / Q000009:adverse effects*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D000097642:GADD45 Proteins
D000409:Alanine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D018797:Cell Cycle Proteins; D007213:Indomethacin; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D015363:Quinolones; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C052785:rebamipide