Circ-Sirt6 promotes the stability and expression of m6A modified Sirt6 mRNA by recruiting IGF2BP2

Coronary artery disease (CAD) is the leading cause of death worldwide. Even though numerous circRNAs have been linked to the formation and progression of CAD, more circular RNA regulators still need to be uncovered in order to enhance the knowledge of the CAD regulatory networks. Microarray analysis was employed to identify aberrantly expressed circRNAs in vascular pathology, and the level of circ-Sirt6 in abnormally proliferated vascular smooth muscle cells (VSMCs) was detected by qRT-PCR. The effects of circ-Sirt6, IGF2BP2, and Sirt6 on the proliferation and migration of VSMCs were examined by EdU incorporation assay and migration assays. The interaction between circ-Sirt6, IGF2BP2, and Sirt6 was verified by RNA pull-down assay, RIP, FISH, and immunofluorescent staining. Dot blot assay and m(6)A-methylated RNA immunoprecipitation-qPCR were performed to confirm that circ-Sirt6 promoted m(6)A modification and stabilization of Sirt6 mRNA. According to our research, circ-Sirt6 expression was markedly downregulated in VSMCs treated with PDGF-BB and carotid artery balloon injury. The in vitro and in vivo proliferation and migration of VSMCs were inhibited by overexpression of circ-Sirt6. Mechanistically, circ-Sirt6 specifically binds to IGF2BP2 and promotes the stability and expression of Sirt6 mRNA by enhancing its m(6)A modification. Our findings highlight the importance of circ-Sirt6-mediated m(6)A in VSMC phenotype switching. Circ-Sirt6 may be a novel biological target for CAD.