LncRNA Gaplinc promotes the pyroptosis of vascular endothelial cells through SP1 binding to enhance NLRP3 transcription in atherosclerosis.

Pyroptosis, characterized by activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and its downstream effector inflammatory factors, has been shown to play a crucial role in atherosclerosis development. Long noncoding RNAs (lncRNAs) are involved in the progression of pyroptosis. However, the role and mechanism of the novel lncRNA gastric adenocarcinoma associated, positive CD44 regulator (Gaplinc), in endothelial cell pyroptosis during atherosclerosis development remain unexplored. Bioinformatics was performed to evaluate dysregulated lncRNAs in atherosclerotic mice fed a high-fat diet. The effect of Gaplinc on atherosclerosis progression in vivo was assessed via Oil Red O staining and fluorescence in situ hybridization. Its function in oxidized low-density lipoprotein (ox-LDL)-induced pyroptosis of endothelial cells was determined through ectopic expression. Additionally, RNA pull-down and immunoprecipitation (RIP) assays were performed to determine Gaplinc and transcription factor SP1 interactions. Then the pyroptosis pathway proteins were analyzed via immunofluorescence and western blotting. We found that lncRNA Gaplinc was highly expressed in ox-LDL-induced endothelial cells as well as in the plaque and plasma of high-fat diet-treated ApoE mice. Gaplinc silencing significantly inhibited endothelial cell pyroptosis and atherosclerotic plaque formation. Mechanistically, Gaplinc could interact with SP1 to bind to the NLRP3 promoter and upregulate the target gene expression of NLRP3, facilitating endothelial cell pyroptosis and atherosclerotic plaque enlargement in high- fat diet-fed mice. In conclusion, our results revealed the underlying mechanism of the lncRNA Gaplinc /SP1/NLRP3 axis in endothelial cell pyroptosis, which may provide new potential targets for the treatment of atherosclerosis.