Hsa_circ_0001304 promotes vascular smooth muscle cell autophagy and neointimal hyperplasia through the YTHDF2/mTOR axis

ABSTRACT Introduction Aberrant autophagy in vascular smooth muscle cells (VSMCs) is associated with the progression of cardiovascular diseases. Recently, circular RNAs (circRNAs) have gradually been reported to regulate autophagy in VSMCs. Objectives This study aims to investigate the role of hsa_circ_0001304 in VSMC autophagy and its underlying mechanism. Methods The combined use of dual-luciferase reporter gene assay, MeRIP-qRT-PCR, RIP-qRT-PCR, etc., was performed to verify the regulatory axis, hsa_circ_0001304/miR-636/YTHDF2/mTOR. Cell autophagy detection was performed to uncover the role of hsa_circ_0001304 on VSMC autophagy. The mouse carotid artery ligation model was conducted to assess the role of hsa_circ_0001304 on vascular neointimal hyperplasia. Results Hsa_circ_0001304 acts as a sponge for miR-636, leading to an increase in the protein levels of YTHDF2. Subsequently, the YTHDF2 promotes the degradation of mTOR mRNA by binding to the latter’s m6A modification sites. Thus, by regulating the miR-636/YTHDF2/mTOR axis, hsa_circ_0001304 activates VSMC autophagy, aggravating neointimal hyperplasia. Conclusion Our findings suggest that autophagy-related hsa_circ_0001304 could serve as a novel therapeutic target for neointimal hyperplasia-related cardiovascular diseases. Including spaces Our study documents a novel VSMC autophagy-related circRNA, namely circ-1304, which activates VSMC autophagy through the miR-636/YTHDF2/mTOR axis, thereby exacerbating neointimal hyperplasia. Targeting autophagy-related circ-1304 may contribute to the treatment of neointimal hyperplasia-associated cardiovascular diseases.