MS4A6A regulates ox-LDL-induced endothelial dysfunction and monocyte adhesion in atherosclerosis via the IKK/NF-kappaB pathway

Atherosclerosis (AS) is characterized by chronic inflammation, which is a significant pathogenic factor of cardiovascular diseases (CVDs). Alleviating endothelial dysfunction and monocyte adhesion are effective ways to halt the development of AS. Membrane Spanning 4-Domains A6A (MS4A6A) is associated with inflammation and primarily regulates immunity and cell signaling. These processes are closely related to the occurrence of AS. However, the specific mechanism remains unclear. In this study, bioinformatics analysis revealed that MS4A6A expression was elevated in human atherosclerotic plaques. Western blot, enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence analyses confirmed that MS4A6A expression correlated with the severity of AS and was significantly expressed in endothelial cells. We determined that MS4A6A was upregulated in atherosclerotic lesions of high-cholesterol diet (HFD) ApoE −/− mice. In a cellular model using human umbilical vein endothelial cells (HUVECs) stimulated with oxidized low-density lipoprotein (ox-LDL), MS4A6A expression exhibited a temporal and concentration-dependent upregulation. Silencing MS4A6A reduced endothelial dysfunction and monocyte adhesion, decreasing the expression of inflammatory factors, adhesion molecules, and reactive oxygen species (ROS). The pathway inhibitor Bay 11-7085 (irreversible inhibitor of IxBalpha phosphorylation) using IκB kinase (IKK) silencing showed that MS4A6A promotes endothelial dysfunction and monocyte adhesion by regulating the IKK/NF-kappaB pathway. This study demonstrated for the first time that MS4A6A facilitates endothelial dysfunction and monocyte adhesion by modulating the IKK/NF-κB signaling pathway, thereby promoting the progression of AS. This study provides a theoretical foundation for utilizing MS4A6A as a biomarker and potential therapeutic target for the prevention and treatment of AS.