Abstract

Background: Although activation of mitogen activated protein kinases (MAPKs) by Helicobacter pylori infection is associated with induction of host angiogenesis, which may contribute to H pylori associated gastric carcinogenesis, the strategy for its prevention has not been identified. As we previously reported a strong inhibitory action of gastric proton pump inhibitors (PPIs) on MAPK extracellular signal regulated kinase (ERK)1/2 phosphorylation, we investigated whether PPIs could suppress the H pylori induced angiogenesis via inhibition of MAPK ERK1/2.

Methods: To address the relationship between H pylori infection and angiogenesis, comparative analysis of density of CD34⁺ blood vessel was performed in tissues obtained from 20 H pylori positive gastritis and 18 H pylori negative gastritis patients. Expression of hypoxia inducible factor 1 (HIF-1α) and vascular endothelial growth factor (VEGF) was tested by reverse transcription-polymerase chain reaction and secretion of interleukin 8, and VEGF was measured by ELISA. To evaluate the direct effect of H pylori infection on the tubular formation of human umbilical vein endothelial cells (HUVEC), an in vitro angiogenesis assay was employed. Activation of MAPK and nuclear factor κB (NFκB) was detected by immunoblotting.

Results:H pylori positive gastritis patients showed a higher density of CD34⁺ blood vessels (mean 40.9 (SEM 4.4)) than H pylori negative gastritis patients (7.2±0.8), which was well correlated with expression of HIF-1α. Conditioned media from H pylori infected gastric epithelial cells directly induced tubular formation of HUVEC and the increase of in vitro angiogenesis was suppressed by PPI treatment. Infection of H pylori significantly upregulated expression of HIF-1α and VEGF in gastric epithelial cells and expression of proangiogenic factors was mediated by MAPK activation and partially responsible for NFκB activation. PPIs effectively inhibited the phosphorylation of MAPK ERK1/2 that is a principal signal for H pylori induced angiogenesis.

Conclusions: The fact that PPIs could downregulate H pylori induced angiogenesis indicates that antiangiogenic treatment using a PPI could be a promising protective therapeutic approach for H pylori associated carcinogenesis.