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

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.

Staphylococcus aureus-mediated blood-brain barrier injury: anin vitrohuman brain microvascular endothelial cell model

“…All samples not used immediately were stored at −80°C until required. For the purpose of bacterial adhesion assays described above, HAECs and BAECs, cultured as previously described (Martin et al, ; Tobin et al, ), were also examined in parallel with HBMvECs. It can also be noted that bacterial adhesion was examined using both static and sheared endothelial cells (0 versus 10 dynes/cm 2 ), with steady non‐pulsatile shear applied by orbital rotation as previously described by Colgan et al ().…”

Helicobacter pylori—An Infectious Risk Factor for Atherosclerosis?

“…There are several possible mechanisms underlying the potential causative role of H. pylori in endothelial dysfunction. First, in vitro studies have revealed that H. pylori-induced endothelial dysfunction may be attributed to VacA 58) , an H. pylori-secreted virulence factor that elicits its effects by modulating plasma and ber of epidemiological studies have investigated the association between H. pylori infection and atherosclerosis and its complications based on the "infection hypothesis." From the pathogenic point of view, chronic H. pylori infection contributes to the initiation and development of atherosclerosis through a variety of mechanisms ( Table 2).…”

The Relationship between Helicobacter pylori Infection and Atherosclerosis: A Meta-analysis

“…There are some proposed mechanisms for the role of H. pylori infection in the development of atherosclerosis. Endothelial dysfunction is one of them and is attributed to vacA and also to the nutritional effect of this microorganism, which usually results in the malabsorption of folate and the vitamins B6 and B 12 and also hyperhomocysteinemia, which is toxic to endothelial cells (41,42).…”