CircMETTL14(11)S upregulated METTL14 and induced CXCR4 to aggravate endothelial inflammation and atherosclerosis

Endothelial inflammatory response can induce a variety of cardiovascular diseases, including atherosclerosis (AS). As a member of the m6A methyltransferase family, methyltransferase like 14 (METTL14) was reported to propel endothelial inflammation and aggravate AS. In this study, qRT-PCR and western blot analyses were performed to detect the RNA and protein levels of genes. To analyze the cyclic structure and localization of circMETTL14(11)S, agarose gel electrophoresis, subcellular fractionation and FISH assays were conducted. The role of circMETTL14(11)S on endothelial inflammation was exposed by monocyte adhesion assay. Luciferase reporter, chromatin immunoprecipitation (ChIP), pull-down and RNA binding protein immunoprecipitation (RIP) assays were conducted to explore the mechanism of circMETTL14(11)S on endothelial inflammation and AS. We found that circMETTL14(11)S (hsa_circ_0125169) expressed highly in TNF-α-induced endothelial inflammation and positively regulated the expression of METTL14 in human umbilical vein endothelial cells (HUVECs). CircMETTL14(11)S facilitated endothelial inflammation of HUVECs by METTL14. Based on the nuclear location, circMETTL14(11)S was found to activate METTL14 transcription via cooperating with SRY-box transcription factor 2 (SOX2). METTL14 accelerated the m6A methylation and stabilization of C-X-C motif chemokine receptor 4 (CXCR4) mRNA. Further, the facilitation of circMETTL14(11)S/METTL14/CXCR4 on TNF-α-induced endothelial inflammation of HUVECs was verified. Collectively, circMETTL14(11)S/METTL14/CXCR4 axis aggravated endothelial inflammation and AS.