Helicobacter pylori urease induces pro‐inflammatory effects and differentiation of human endothelial cells: Cellular and molecular mechanism

Abstract

Background Helicobacter pylori urease (HPU) is a key virulence factor that enables bacteria to colonize and survive in the stomach. We early demonstrated that HPU, independent of its catalytic activity, induced inflammatory and angiogenic responses in vivo and directly activated human neutrophils to produce reactive oxygen species (ROS). We have investigated the effects of HPU on endothelial cells, focusing on the signaling mechanism involved. Methods Monolayers of human microvascular endothelial cells (HMEC‐1) were stimulated with HPU (up to 10 nmol/L): Paracellular permeability was accessed through dextran‐FITC passage. NO and ROS production was evaluated using intracellular probes. Proteins or mRNA expressions were detected by Western blotting and fluorescence microscopy or qPCR assays, respectively. Results Treatment with HPU enhanced paracellular permeability of HMEC‐1, preceded by VE‐cadherin phosphorylation and its dissociation from cell‐cell junctions. This caused profound alterations in actin cytoskeleton dynamics and focal adhesion kinase (FAK) phosphorylation. HPU triggered ROS and nitric oxide (NO) production by endothelial cells. Increased intracellular ROS resulted in nuclear factor kappa B (NF‐κB) activation and upregulated expression of cyclooxygenase‐2 (COX‐2), hemeoxygenase‐1 (HO‐1), interleukin‐1β (IL‐1β), and intercellular adhesion molecule‐1 (ICAM‐1). Higher ICAM‐1 and E‐selectin expression was associated with increased neutrophil adhesion on HPU‐stimulated HMEC monolayers. The effects of HPU on endothelial cells were dependent on ROS production and lipoxygenase pathway activation, being inhibited by esculetin. Additionally, HPU improved vascular endothelial growth factor receptor 2 (VEGFR‐2) expression. Conclusion The data suggest that the pro‐inflammatory properties of HPU drive endothelial cell to a ROS‐dependent program of differentiation that contributes to the progression of H pylori infection.

Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity

“…The activation of this pathway increases HIF-α expression [22]. Moreover, H. pylori urease was found to drive the differentiation of endothelial cells by producing reactive oxygen species and activating the lipoxygenase pathway via pro-inflammatory properties, contributing to H. pylori infection progression to gastric carcinogenesis [23]. Furthermore, H. pylori urease was shown to bind to major histocompatibility complex (MHC) class II molecules and induce cell apoptosis [24].…”

Focal Adhesion Kinase Inhibitor Inhibits the Oxidative Damage Induced by Central Venous Catheter via Abolishing Focal Adhesion Kinase-Protein Kinase B Pathway Activation

“…FAK is reported to be involved in the occurrence and development of oxidative stress and inflammation [ 16 ]. When noxious stimuli act on cells, phosphorylated FAK or part of FAK-related signaling pathways can upregulate intracellular ROS levels, leading to abnormal cellular oxidative metabolism [ 28 , 29 ]. Y15, an FAK inhibitor, can target the Y397 site of FAK and inhibits its autophosphorylation [ 21 ], thereby regulating NO, ROS, MDA, and SOD levels [ 30 , 31 ] via inhibiting of Src/FAK, PI3K/Akt/endothelial nitric oxide synthase (eNOS), and FAK/Akt/eNOS signaling pathways [ 19 , 20 ] and resulting in reduced oxidative stress [ 32 ].…”

Using Probiotics as Supplementation for Helicobacter pylori Antibiotic Therapy

“…Ammonium ions can destroy the integrity of the connection between gastric epithelial cells, while carbon dioxide supports bacteria resistance to damage from nitric oxide metabolites and peroxynitrite produced by phagocytic cells [26]. Urease also induces inflammation and angiogenesis in vivo independently of its catalytic activity and directly activates human neutrophils to produce reactive oxygen species, thereby injuring the host body [49].…”