Abstract
BACKGROUND: Helicobacter pylori (H. pylori) infection increases the risk for atherosclerosis, and ROS are critical to endothelial dysfunction and atherosclerosis. CagA is a major H. pylori virulence factor associated with atherosclerosis. The present study aimed to test the hypothesis that CagA(+) H. pylori effectively colonizes gastric mucosa, and CagA(+) H. pylori, but not CagA(-) H. pylori, infection impairs endothelial function through exosomes-mediated ROS formation. METHODS: C57BL/6 were used to determine the colonization ability of CagA(+) H. pylori and CagA(-) H. pylori. ROS production, endothelial function of thoracic aorta and atherosclerosis were measured in CagA(+) H. pylori and CagA(-) H. pylori infected mice. Exosomes from CagA(+) H. pylori and CagA(-) H. pylori or without H. pylori infected mouse serum or GES-1 were isolated and co-cultured with bEND.3 and HUVECs to determine how CagA(+) H. pylori infection impairs endothelial function. Further, GW4869 was used to determine if CagA(+) H. pylori infection could lead to endothelial dysfunction and atherosclerosis through an exosomes-mediated mechanism. RESULTS: CagA(+) H. pylori colonized gastric mucosa more effectively than CagA(-) H. pylori in mice. CagA(+) H. pylori, not CagA(-) H. pylori, infection significantly increased aortic ROS production, decreased ACh-induced aortic relaxation, and enhanced early atherosclerosis formation, which were prevented with N-acetylcysteine treatment. Treatment with CagA-containing exosomes significantly increased intracellular ROS production in endothelial cells and impaired their function. Inhibition of exosomes secretion with GW4869 effectively prevented excessive aortic ROS production, endothelial dysfunction, and atherosclerosis in mice with CagA(+) H. pylori infection. CONCLUSION: These data suggest that CagA(+) H. pylori effectively colonizes gastric mucosa, impairs endothelial function, and enhances atherosclerosis via exosomes-mediated ROS formation in mice.