A possible involvement of Nrf2-mediated heme oxygenase-1 up-regulation in protective effect of the proton pump inhibitor pantoprazole against indomethacin-induced gastric damage in rats
- Authors
- Lee, Ho-Jae; Han, Young-Min; Kim, Eun-Hee; Kim, Yoon-Jae; Hahm, Ki-Baik
- Issue Date
- 16-Oct-2012
- Publisher
- BMC
- Keywords
- Heme oxygenase-1; Proton pump inhibitor; NSAIDs-induced gastropathy; Nrf2
- Citation
- BMC GASTROENTEROLOGY, v.12
- Journal Title
- BMC GASTROENTEROLOGY
- Volume
- 12
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/16083
- DOI
- 10.1186/1471-230X-12-143
- ISSN
- 1471-230X
- Abstract
- Background: Proton pump is an integral membrane protein that is ubiquitous ATP binding cassette (ABC) involved in many transport processes in all living organisms, among which a specialized form of pump, so called p-type proton pump, exists in the parietal cells of stomach. Though proton pump inhibitors (PPIs) are frequently prescribed to prevent nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage, the acid suppressive actions do not suffice to explain. Methods: In order to document the effects of pantoprazole, one of PPIs, on the NSAIDs-induced gastric damage, in vitro and in vivo studies were performed. Immunocytochemistry, Western blot analysis, electrophoretic mobility shift assay and RT-PCR were conducted to evaluate the induction of heme oxygenase-1 (HO-1) through Nrf2 activation in normal gastric mucosal RGM-1 cells or in vivo stomach tissues from rats treated with indomethacin and/or pantoprazole. Results: Pantoprazole activated Nrf2 through inactivation of Keap1, after which the expression of HO-1 was significantly increased in a dose-dependent manner in RGM-1 cells. Increased ARE-DNA binding activity was observed maximally at 1 h with 300 mu M of pantoprazole. The expression of HO-1 induced by pantoprazole was significantly associated with the increased in vitro tube formation (P < 0.05) and angiogenic factors including VEGF, bFGF, and HIF-1 alpha. Indomethacin markedly increased the expressions of TNF-alpha, IL-1 beta, IL-8, NOX-1, ICAM-1 and VCAM, whereas pantoprazole significantly decreased the expressions of indomethacin-induced these inflammatory mediators in accord with pantoprazole-induced HO-1 (P < 0.05) as documented with HO-1 inhibitor. In vivo model of indomethacin-induced gastric damage could validate in vitro-drawn results that pantoprazole remarkably protected against indomethacin-induced gastric damage, in which zinc protoporphyrin (5 mg/kg, ip) significantly abolished the protective efficacy of pantoprazole. Conclusion: These results demonstrate that Nrf2-mediated HO-1 induction of PPIs afforded a significant protective effect against NSAIDs-induced gastric damage beyond acid suppressive actions.
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