Objective: Heat shock proteins (HSPs) are crucial for the maintenance of cellular integrity during normal cell growth as well as pathophysiological conditions. While acting as molecular chaperones with their folding activities, HSPs play a cytoprotective role to rescue epithelial cells from several gastric damages including non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori. Since the exact relationship between HSP27 phosphorylation and biological function remains unknown in NSAID-induced gastropathy, we hypothesized that revaprazan, a novel acid pump antagonist, can secure significant cytoprotection from NSAID damages through HSP27 accentuation.
Methods: We evaluated protective actions of revaprazan against either in vivo animal model of indomethacin induced gastropathy or in vitro cell model focused on HSP27 expression and activation.
Results: Indomethacin induced significant cytotoxicities accompanied with phosphorylated HSP27 and attenuated levels of HSP27 in the in vitro cell experiment and revaprazan administration protected stomach from indomethacin-induced gastric damages in accordance with HSP27 dephosphorylation in the in vivo animal experiment. HSP27 siRNA abolished these cytoprotective privileges of revaprazan. Indomethacin, 40 mg/kg, po, administration provoked significant levels of gastric damages accompanied with decrement in HSP27, while rats administrated with revaprazan prior to indomethacin imposed the accentuation of HSP27, of which levels were significantly correlated with the prevention of the indomethacin-induced gastric damages.
Conclusion: HSP27 phosphorylation with resultant decrease in HSP27 level was one of the mechanisms of indomethacin-induced cytotoxicity, of which post-translational modifications were prevented with revaprazan administration in the presence of indomethacin. Therefore, acid pump antagonist could be a choice for the prevention of NSAID-induced gastropathy backed up with distinctive cytoprotective action beyond acid suppressor.
© 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.