GALNT4 promotes the endothelial cell inflammatory response via the NF-κB signaling pathway

Abstract

Abstract Background Atherosclerosis (AS) is a chronic inflammatory disease caused by dysfunction of vascular endothelial cells (ECs). Polypeptide N-acetylgalactosaminyl -transferase 4 (GALNT4) modifies target proteins via O-N-acetylgalactosamine (O-GalNAc) glycosylation, which is known to play a crucial role in regulating the inflammatory response in AS, but its exact function in ECs is yet to be determined. Objective This study aims to investigate the effect of GALNT4 on endothelial cell inflammation and AS. Methods and results We found GALNT4 expression increased in ECs exposed to pro-inflammatory stimuli. GALNT4 over-expression led to upregulation of pro-inflammatory molecules such as ICAM-1, VCAM-1, and MCP-1, which promoted the adhesion of leukocytes to ECs and trans-endothelial migration. Conversely, knockdown of GALNT4 reduced the expression of pro-inflammatory molecules induced by TNF-α. The study also observed that over-expression of GALNT4 increased the binding of NF-κB to the promoter of ICAM-1, VCAM-1, and MCP-1, while GALNT4 knockdown had the opposite effect. Additionally, GALNT4 degraded IκBα and facilitated the translocation of the NF-κB p65 subunit, thereby activating the NF-κB pathway. Finally, GALNT4-mediated endothelial cell inflammation was reduced by the NF-κB inhibitor PDTC and knockdown of the NF-κB p65 subunit, indicating that the NF-κB pathway plays a vital role in regulating GALNT4-mediated expression of adhesion molecules and chemokines. Conclusion We provide evidence that GALNT4 promotes the adherence of monocytes to ECs and their trans-endothelial migration via the NF-κB signaling pathway. GALNT4 could be a potential therapeutic target for AS.