**4.3 Potential mechanisms for the effect of** *H. pylori* **infection on endothelial function**

It is important to know how *H. pylori* infection leads to endothelial dysfunction. *In vitro* study using bovine aortic endothelial cells (BAECs) showed that treatment of BAECs with *H. pylori*-conditioned medium from *H. pylori* 60190 (vacuolating cytotoxin A) significantly decreased the proliferation, tube formation, and migration of the cells (by up to 44%, 65%, and 28%, respectively) through VacA-dependent reduction in the production of endothelial nitric oxide (NO) [62]. Culture of human umbilical vein endothelial cells (HUVECs) with *H. pylori* significantly inhibited the proliferation, migration, and tube formation of HUVECs, and increased the production of the inflammatory factor Chitinase 3 Like 1 (CHI3L1) and phosphorylated p38 in endothelial cells associated with an increased expression of GATA3. Increased levels of GATA3 and CHI3L1 were also found in the arteries of mice with *H. pylori* infection. Knockdown of GATA3 could prevent *H. pylori*-induced dysfunction of HUVECs. These findings suggest that *H. pylori* might impair endothelial function through increased expression of GATA3 and production of CHI3L1 [63].

*H. pylori* urease (HPU) is considered a key virulence factor that enables bacteria to colonize and survive in the stomach. It has been shown that HPU could trigger the production of reactive oxygen species (ROS) in endothelial cells. Increased intracellular ROS could lead to activation of nuclear factor kappa B (NF-κB) and upregulate expressions of cyclooxygenase-2, hemeoxygenase-1, interleukin (IL)-1β, and ICAM-1, thus increasing oxidative stress and endothelial dysfunction [64]. *H. pylori* infection of primary human endothelial cells is reported to stimulate secretion of important inflammatory cytokines, IL-6 and IL-8 (especially IL-8) in endothelial cells [65]. Treatment of HUVECs with different CagA positive and negative *H. pylori* derived products could enhance the expressions of microRNAs (miRNAs) including miR-21, miR-155, and miR-663 in the cells that are associated with inflammation, apoptosis and necrosis of the cell [66]. Recently, it was reported that *H. pylori* infection could impair endothelial function through exosomesmediated mechanism [55]. This will be discussed in details below.
