Heme Oxygenase-1 Protects Gastric Mucosal Cells against Non-steroidal Anti-inflammatory Drugs

• Published in: The Journal of biological chemistry 2006-11, Vol.281 (44), p.33422-33432
• Main Authors: Aburaya, Mayuko, Tanaka, Ken-Ichiro, Hoshino, Tatsuya, Tsutsumi, Shinji, Suzuki, Keitarou, Makise, Masaki, Akagi, Reiko, Mizushima, Tohru
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Gastric Mucosa - cytology; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Guinea Pigs; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Indomethacin - pharmacology; Male; Metalloporphyrins - pharmacology; NF-E2-Related Factor 2 - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Promoter Regions, Genetic - genetics; Rats; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M602074200

Gastric mucosal cell death by non-steroidal anti-inflammatory drugs (NSAID11113) is suggested to be involved in NSAID-induced gastric lesions. Therefore, cellular factors that suppress this cell death are important for protection of the gastric mucosa from NSAIDs. Heme oxygenase-1 (HO-1) is up-regulated by various stressors and protects cells against stressors. Here, we have examined up-regulation of HO-1 by NSAIDs and the contribution of HO-1 to the protection of gastric mucosal cells against NSAIDs both in vitro and in vivo. In cultured gastric mucosal cells, all NSAIDs tested up-regulated HO-1. In rats, orally administered indomethacin up-regulated HO-1, induced apoptosis, and produced lesions at gastric mucosa. An inhibitor of HO-stimulated NSAID-induced apoptosis in vitro and in vivo and also stimulated NSAID-produced gastric lesions, suggesting that NSAID-induced up-regulation of HO-1 protects the gastric mucosa from NSAID-induced gastric lesions by inhibiting NSAID-induced apoptosis. Indomethacin activated the HO-1 promoter and caused nuclear accumulation of NF-E2-related factor 2 (Nrf2), a transcription factor for the HO-1 gene. Examination of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and experiments with its inhibitor strongly suggest that the nuclear accumulation of Nrf2 and resulting up-regulation of HO-1 by NSAIDs is mediated through NSAID-dependent activation (phosphorylation) of p38 MAPK. This is the first report showing the protective role of HO-1 against irritant-induced gastric lesions.