Helicobacter pylori-induced inhibition of vascular endothelial cell functions: a role for VacA-dependent nitric oxide reduction

Authors

Nicholas P. Toblin, Dublin City University
Gary Henehan, Technological University DublinFollow
Ronan P. Murphy, Dublin City University
John P. Atherton, University Hospital Nottingham
Anthony F. Guinan, Dublin City University
Steven W. Kerrigan, Royal College of Surgeons in Ireland
Dermot Cox, Royal College of Surgeons in Ireland
Paul A. Cahill, Dublin City University
Philip M. Cummins, Dublin City UniversityFollow

Author ORCID Identifier

https://orcid.org/ 0000-0001-9208-6937

Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1. NATURAL SCIENCES, 1.6 BIOLOGICAL SCIENCES, Cell biology,, Microbiology

Publication Details

American Journal of Physiology - Heart and Circulatory Physiology

https://journals.physiology.org/doi/full/10.1152/ajpheart.00240.2008

https://doi.org/10.1152/ajpheart.00240.2008

Abstract

Epidemiological and clinical studies provide compelling support for a causal relationship between Helicobacter pylori infection and endothelial dysfunction, leading to vascular diseases. However, clear biochemical evidence for this association is limited. In the present study, we have conducted a comprehensive investigation of endothelial injury in bovine aortic endothelial cells (BAECs) induced by H. pylori-conditioned medium (HPCM) prepared from H. pylori 60190 [vacuolating cytotoxin A (Vac(+))]. BAECs were treated with either unconditioned media, HPCM (0-25% vol/vol), or Escherichia coli-conditioned media for 24 h, and cell functions were monitored. Vac(+) HPCM significantly decreased BAEC proliferation, tube formation, and migration (by up to 44%, 65%, and 28%, respectively). Posttreatment, we also observed sporadic zonnula occludens-1 immunolocalization along the cell-cell border, and increased BAEC permeability to FD40 Dextran, indicating barrier reduction. These effects were blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid (VacA inhibitor) and were not observed with conditioned media prepared from either VacA-deleted H. pylori or E. coli. The cellular mechanism mediating these events was also considered. Vac(+) HPCM (but not Vac(-)) reduced nitric oxide (NO) by >50%, whereas S-nitroso-N-acetylpenicillamine, an NO donor, recovered all Vac(+) HPCM-dependent effects on cell functions. We further demonstrated that laminar shear stress, an endothelial NO synthase/NO stimulus in vivo, could also recover the Vac(+) HPCM-induced decreases in BAEC functions. This study shows, for the first time, a significant proatherogenic effect of H. pylori-secreted factors on a range of vascular endothelial dysfunction markers. Specifically, the VacA-dependent reduction in endothelial NO is indicated in these events. The atheroprotective impact of laminar shear stress in this context is also evident.

DOI

https://doi.org/10.1152/ajpheart.00240.2008

Recommended Citation

Tobin NP, Henehan GT, Murphy RP, Atherton JC, Guinan AF, Kerrigan SW, Cox D, Cahill PA, Cummins PM. Helicobacter pylori-induced inhibition of vascular endothelial cell functions: a role for VacA-dependent nitric oxide reduction. Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1403-13. doi: 10.1152/ajpheart.00240.2008. Epub 2008 Jul 25. PMID: 18660451.