Exosomal CagA derived from Helicobacter pylori-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis

J Mol Cell Cardiol. 2019 Oct:135:40-51. doi: 10.1016/j.yjmcc.2019.07.011. Epub 2019 Jul 25.

Abstract

Background: Seroepidemiological studies have highlighted a positive relation between CagA-positive Helicobacter pylori (H. pylori), atherosclerosis and related clinic events. However, this link has not been well validated. The present study was designed to explore the role of H. pylori PMSS1 (a CagA-positive strain that can translocate CagA into host cells) and exosomal CagA in the progression of atherosclerosis.

Methods: To evaluate whether H. pylori accelerates or even induces atherosclerosis, H. pylori-infected C57/BL6 mice and ApoE-/- mice were maintained under different dietary conditions. To identify the role of H. pylori-infected gastric epithelial cells-derived exosomes (Hp-GES-EVs) and exosomal CagA in atherosclerosis, ApoE-/- mice were given intravenous or intraperitoneal injections of saline, GES-EVs, Hp-GES-EVs, and recombinant CagA protein (rCagA).

Findings: CagA-positive H. pylori PMSS1 infection does not induce but promotes macrophage-derived foam cell formation and augments atherosclerotic plaque growth and instability in two animal models. Meanwhile, circulating Hp-GES-EVs are taken up in aortic plaque, and CagA is secreted in Hp-GES-EVs. Furthermore, the CagA-containing EVs and rCagA exacerbates macrophage-derived foam cell formation and lesion development in vitro and in vivo, recapitulating the pro-atherogenic effects of CagA-positive H. pylori. Mechanistically, CagA suppresses the transcription of cholesterol efflux transporters by downregulating the expression of transcriptional factors PPARγ and LXRα and thus enhances foam cell formation.

Interpretation: These results may provide new insights into the role of exosomal CagA in the pathogenesis of CagA-positive H. pylori infection-related atherosclerosis. It is suggested that preventing and eradicating CagA-positive H. pylori infection could reduce the incidence of atherosclerosis and related events.

Keywords: Atherosclerosis; CagA; Exosomes; Foam cell formation; Helicobacter pylori; Macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / metabolism*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / microbiology
  • Atherosclerosis / pathology
  • Bacterial Proteins / metabolism*
  • Epithelial Cells / metabolism*
  • Epithelial Cells / microbiology
  • Epithelial Cells / pathology
  • Foam Cells / metabolism*
  • Foam Cells / microbiology
  • Foam Cells / pathology
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / microbiology
  • Gastric Mucosa / pathology
  • Helicobacter Infections / metabolism*
  • Helicobacter Infections / pathology
  • Helicobacter pylori / metabolism*
  • Mice

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • cagA protein, Helicobacter pylori