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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1403    most recent 00240.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Tobin, N. P. Articles by Cummins, P. M. Search for Related Content PubMed PubMed Citation Articles by Tobin, N. P. Articles by Cummins, P. M.

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

¹School of Biotechnology, Dublin City University; ²School of Food Science and Environmental Health, Dublin Institute of Technology; ³Wolfson Digestive Diseases Centre, University Hospital Nottingham; and ⁴Molecular and Cellular Therapeutics, Royal College of Surgeons of Ireland, Dublin, Ireland

Submitted 7 March 2008 ; accepted in final form 23 July 2008

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.

vacuolating cytotoxin A; shear stress