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Original Article

Mitochondrial Cytochrome c Release and Caspase-3-Like Protease Activation During Indomethacin-Induced Apoptosis in Rat Gastric Mucosal Cells

Yasuyoshi Fujii^*,, Tatsuya Matsura^*,1, Masachika Kai^*, Hirofumi Matsui, Hironaka Kawasaki and Kazuo Yamada^*

^* Department of Biochemistry and
Second Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683–8503, Japan; and
Riken Cell Bank, Tsukuba 305–0074, Japan

Indomethacin (IND), a nonsteroidal anti-inflammatory drug, has been known to cause gastric mucosal injury as a side effect. Using a rat gastric mucosal cell line, RGM1, we determined whether apoptosis is involved in IND-mediated gastropathy, and whether caspase activation and mitochondrial cytochrome c release play an important role in producing apoptosis of IND-treated RGM1 cells in the presence of serum. IND caused caspase-3-like protease activation followed by apoptosis in a dose- and time-dependent manner. Caspase-1-like protease activity did not change during IND-induced apoptosis. IND also increased mitochondrial cytochrome c release in a time-dependent fashion. Mitochondrial cytochrome c efflux occurred just before or at the same time as caspase-3-like protease activation, and preceded the increase in apoptotic cell numbers. Z-VAD-FMK, a caspase inhibitor, inhibited both the increase in caspase-3-like protease activity and apoptosis in IND-treated RGM1 cells but did not affect caspase-1-like protease activity or mitochondrial cytochrome c release. These observations suggest that the apoptosis of gastric mucosal cells could be involved in IND-induced gastropathy, that cytochrome c is released from mitochondria into the cytosol during the early phase of IND-mediated apoptosis, and that subsequent activation of caspase-3-like protease, but not caspase-1-like protease, is required for the execution of apoptosis.

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