Abstract

Atherosclerosis (AS) is a leading cause of cardiovascular-related death worldwide. The role and regulatory mechanism of GAS6-AS2 in AS remain unclear. To investigate the diagnostic/prognostic value of GAS6-AS2 in AS and clarify its molecular mechanism. 107 AS patients and 105 healthy controls were included. The levels of GAS6-AS2, miR-138-5p, and mRNA were measured using RT-qPCR. ROC curve, K-M survival analysis, and Cox regression were performed to evaluate the diagnostic and prognostic value of GAS6-AS2. Bioinformatics prediction and dual-luciferase reporter assay were performed to verify the regulatory axis. Ox-LDL-induced VSMCs were used to construct an AS cell model. The biological functions were assessed using CCK-8, SA-β-Gal, and ELISA. GAS6-AS2 expression was significantly increased in AS patients and in VSMCs treated with ox-LDL, and it showed high diagnostic accuracy and risk prediction for patients with AS. Knockdown of GAS6-AS2 reduced SA-β-Gal-positive cells, downregulated the expression of senescence-related genes and proteins (p16, p21, p53), and decreased the levels of inflammatory factors (IL-6, IL-1β) in ox-LDL-induced VSMCs. Mechanistically, GAS6-AS2 directly bound to miR-138-5p and inhibited its expression, while miR-138-5p targeted AKT1 to suppress its expression. Rescue experiments confirmed that the GAS6-AS2/miR-138-5p/AKT1 axis mediated ox-LDL-induced VSMC senescence and inflammation. GAS6-AS2 is a potential diagnostic and prognostic biomarker for AS. It regulates ox-LDL-induced VSMC senescence and inflammatory response through the sponging of miR-138-5p to upregulate AKT1, providing a novel molecular target for AS treatment.