Original Articles
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Sep 21, 2009; 15(35): 4392-4401
Published online Sep 21, 2009. doi: 10.3748/wjg.15.4392
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
Stephanie Schulz-Geske, Kati Erdmann, Nina Grosser, Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany
Ronald J Wong, David K Stevenson, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, United States
Henning Schröder, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States
Author contributions: Schulz-Geske S performed the majority of experiments and drafted the manuscript; Erdmann K was involved in HO-1 mRNA analysis and editing the manuscript; Wong RJ designed the BLI measurements and was involved in interpretation and editing the manuscript; Stevenson DK provided tools and financial support for the BLI measurement and edited the manuscript; Schröder H made substantial contributions to the study concept and edited the manuscript; Grosser N conceptualized the study and drafted the manuscript.
Supported by The German Academic Exchange Program (DAAD, S.S.G.)
Correspondence to: Dr. Nina Grosser, Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany. nina.grosser@pharmazie.uni-halle.de
Telephone: +49-345-5525165 Fax: +49-345-5527025
Received: March 9, 2009
Revised: August 17, 2009
Accepted: August 24, 2009
Published online: September 21, 2009
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.

Keywords: Antioxidants, Ferritin, Heme oxygenase-1, Lansoprazole, Reactive oxygen species