PAI-1 deficiency increases the trophic effects of hypergastrinemia in the gastric corpus mucosa

Peptides. 2016 May:79:83-94. doi: 10.1016/j.peptides.2016.03.016. Epub 2016 Mar 30.

Abstract

The gastric hormone gastrin plays a role in organizing the gastric mucosa. Gastrin also regulates the expression of genes that have important actions in extracellular matrix modelling, including plasminogen activator inhibitor (PAI)-1 which is part of the urokinase plasminogen activator (uPA) system. The uPA system (including PAI-1) is associated with cancer progression, fibrosis and thrombosis. Its biological role in the stomach and molecular mechanisms of action are not well understood. The aim of this study was to examine the effect of PAI-1 on the trophic changes observed in gastric corpus mucosa in hypergastrinemia using PAI-1 and/or HK-ATPase beta subunit knockout (KO) mice. HK-ATPase beta subunit KO mice were used as a model of hypergastrinemia. In 12 month old female mice, intragastric acidity and plasma gastrin were measured. The stomachs were examined for macroscopic and histological changes. In mice null for both PAI-1 and HK-ATPase beta (double KO), there was exaggerated hypergastrinemia, increased stomach weight and corpus mucosal thickness, and more pronounced trophic and architectural changes in the corpus compared with HK-ATPase beta KO mice. Genome-wide microarray expression data for the gastric corpus mucosa showed a distinct gene expression profile for the HK-ATPase beta KO mice; moreover, enrichment analysis revealed changes in expression of genes regulating intracellular processes including cytoskeleton remodelling, cell adhesion, signal transduction and epithelial-to-mesenchymal transition (EMT). Genes differentially expressed in the double KO compared with HK-ATPase beta KO mice included the transcription factor Barx2 and the chromatin remodeler gene Tet2, which may be involved in both normal gastric physiology and development of gastric cancer. Based on the present data, we suggest that PAI-1 plays a role in maintaining gastric mucosal organization in hypergastrinemia.

Keywords: Gastric mucosa; Gastric proton pump; Gastrin; Plasminogen activator inhibitor-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enterochromaffin-like Cells / enzymology
  • Enterochromaffin-like Cells / pathology
  • Female
  • Gastric Mucosa / enzymology*
  • Gastric Mucosa / pathology
  • Gastrins / blood*
  • H(+)-K(+)-Exchanging ATPase / genetics
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pyloric Antrum / enzymology
  • Pyloric Antrum / pathology
  • Serpin E2 / genetics*
  • Serpin E2 / metabolism

Substances

  • Gastrins
  • Serpin E2
  • Serpine2 protein, mouse
  • H(+)-K(+)-Exchanging ATPase