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

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 NADPHmediated 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.

The Proton-Pump Inhibitor Lansoprazole Enhances Amyloid Beta Production

“…As expected, cells treated with the γ–secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) showed negligible levels of Aβ. These results indicate that lansoprazole treatment increase Aβ production at commonly used concentrations [32], [33], [34], [35], [36], which in turn are comparable to other Aβ inducers such as the calcium ionophore A23187, which increases the production of Aβ approximately 3-fold [37], or caffeine (at millimolar concentrations), that increases Aβ levels until 4-fold [38]. In addition, we have observed an Aβ42 increase of over 250% compared to vehicle in cell cultures treated at 50 µM lansoprazole, while fenofibrate, a potent Aβ42 raising Aβ38 lowering compound, generates an increase of 125% at the same concentration [39].…”

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“…Many authors studied the whole literature concerning the relation between iron accumulation and the increased occurrence of cardiovascular diseases 139 ; even though this topic is still under discussion, the new techniques in the dosage of free NTBI highlighted the role played by free hemoglobin and HMOX1 (heme oxygenase) in the regulation of the cellular iron and the inducing effect of some drugs on the HMOX1, such as statins, aspirin and more particularly lansoprazole, etc. 140,141 , their protective effect in the vessel endothelium 142 and, lastly, the challenge of the chelating therapy in local siderosis 143 ; all of the abovementioned factors seem to corroborate the hypothesis that the iron overload is toxic in cardiovascular diseases.…”

The role of free iron in cardiovascular diseases. Part II

“…Many authors studied the whole literature concerning the relation between iron accumulation and the increased occurrence of cardiovascular diseases 139 ; even though this topic is still under discussion, the new techniques in the dosage of free NTBI highlighted the role played by free hemoglobin and HMOX1 (heme oxygenase) in the regulation of the cellular iron and the inducing effect of some drugs on the HMOX1, such as statins, aspirin and more particularly lansoprazole, etc. 140,141 , their protective effect in the vessel endothelium 142 and, lastly, the challenge of the chelating therapy in local siderosis 143 ; all of the abovementioned factors seem to corroborate the hypothesis that the iron overload is toxic in cardiovascular diseases.…”