Role of Outer Membrane Vesicles From Helicobacter pylori in Atherosclerosis

Abstract

Infection is thought to be involved in the pathogenesis of atherosclerosis. Studies have shown the association between helicobacter pylori (H. pylori) and coronary artery disease. It is interesting to find H. pylori DNA and cytotoxin-associated gene A (CagA) protein in atherosclerotic plaque. Outer membrane vesicles (OMVs), secreted by H. pylori, exert effects in the distant organ or tissue. However, whether or not OMVs from H. pylori are involved in the pathogenesis of atherosclerosis remains unknown. Our present study found that treatment with OMVs from CagA-positive H. pylori accelerated atherosclerosis plaque formation in ApoE–/– mice. H. pylori-derived OMVs inhibited proliferation and promoted apoptosis of human umbilical vein endothelial cells (HUVECs), which was also reflected in in vivo studies. These effects were normalized to some degree after treatment with lipopolysaccharide (LPS)-depleted CagA-positive OMVs or CagA-negative OMVs. Treatment with H. pylori-derived OMVs increased reactive oxygen species (ROS) levels and enhanced the activation of nuclear factor-κB (NF-κB) in HUVECs, which were reversed to some degree in the presence of a superoxide dismutase mimetic TEMPOL and a NF-κB inhibitor BAY11-7082. Expressions of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), two inflammatory factors, were augmented after treatment with OMVs from H. pylori. These suggest that H. pylori-derived OMVs accelerate atherosclerosis plaque formation via endothelium injury. CagA and LPS from H. pylori-OMVs, at least in part, participate in these processes, which may be involved with the activation of ROS/NF-κB signaling pathway. These may provide a novel strategy to reduce the incidence and development of atherosclerosis.

Helicobacter Pylori Virulence Factor Cytotoxin-Associated Gene A (CagA) Induces Vascular Calcification in Coronary Artery Smooth Muscle Cells

“…However, one study detected CagA in the vasa vasorum of human aortic sections from CagA-positive patients using immunohistochemical staining [ 34 ], which further indicates that systemic occurrence of CagA is possible and relevant in patients. In vivo mouse models using CagA-containing outer membrane vesicles of H. pylori as treatment accelerated atherosclerosis when administrated intra-gastrically [ 35 ].…”

“…Furthermore, CagA is pro-inflammatory and activates NF-kB both through the PI3K/Akt pathway as well as the STAT3/JAK2 pathway [ 40 ]. Both pathways have been shown to be activated in vascular endothelial cells following CagA stimulation [ 35 , 42 ]. The same pathways may have induced the pro-inflammatory effects in CASMCs observed in this study to stimulate their trans-differentiation toward an osteogenic and/or macrophage-like phenotype.…”

Extracellular Vesicles: Recent Insights Into the Interaction Between Host and Pathogenic Bacteria

“…Moreover, CagA and LPS from bEVs might injure the endothelium and promote atherosclerotic plaque formation. These processes might be associated with the activation of the ROS/NF-κB signaling pathway ( 76 ).…”

Helicobacter pylori‐derived outer membrane vesicles contribute to Alzheimer's disease pathogenesis via C3‐C3aR signalling

“…OMVs derived from H. pylori exert immunomodulatory effects by inducing the production of proinflammatory cytokines such as IL‐6 and TNF, and by promoting apoptosis of gastric epithelial cells and immune cells. These inflammatory responses may further accelerate the development of H. pylori infection (Chmiela et al., 2018 ; Wang et al., 2021 ). In addition, H. pylori OMVs are also found to induce apoptosis of human umbilical vein endothelial cells, which may promote the formation of atherosclerotic plaques (Wang et al., 2021 ).…”

“…These inflammatory responses may further accelerate the development of H. pylori infection (Chmiela et al., 2018 ; Wang et al., 2021 ). In addition, H. pylori OMVs are also found to induce apoptosis of human umbilical vein endothelial cells, which may promote the formation of atherosclerotic plaques (Wang et al., 2021 ). However, no study has attempted to determine their role in AD development and progression.…”