Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction

Stephanie Schulz-Geske, Kati Erdmann, Ronald J. Wong, David K. Stevenson, Henning Schröder, Nina Grosser

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

AIM: To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages. METHODS: Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species (ROS) formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed using in vivo bioluminescence imaging. RESULTS: Lansoprazole increased HO-1 mRNA levels in endothelial cells and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH-mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity. CONCLUSION: Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002.

Original languageEnglish (US)
Pages (from-to)4392-4401
Number of pages10
JournalWorld journal of gastroenterology
Volume15
Issue number35
DOIs
StatePublished - Dec 21 2009

Keywords

  • Antioxidants
  • Ferritin
  • Heme oxygenase-1
  • Lansoprazole
  • Reactive oxygen species

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