CircTLK1: A novel regulator involved in VSMC phenotypic switching and the developmental process of atherosclerosis

Abstract Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for atherosclerosis development. Circular RNA (circRNA) is a specific non‐coding RNA that is produced as a closed‐loop structure in mammals, and its specific expression pattern is closely related to its cell type and tissue. To clarify the roles of circTLK1 in VSMC phenotypic switching, we performed qRT‐PCR, immunoblotting, and immunostaining. qRT‐PCR revealed that circTLK1 was upregulated in both mouse models of atherosclerosis in vivo and PDGF (platelet‐derived growth factor)–BB‐induced VSMCs in vitro. Furthermore, the overexpression of circTLK1 promoted PDGF‐BB‐induced VSMC phenotypic switching. Conversely, experiments performed in vivo demonstrate that the knockdown of SMC‐specific circTLK1 led to a reduction in the development of atherosclerosis. The relationship between circTLK1 and miR‐513a‐3p and Krüppel‐like factor 4 (KLF4) was detected by RNA immunoprecipitation (RIP), luciferase reporter assay, RNA pull‐down, and RNA fluorescence in situ hybridization (RNA FISH). Mechanistically, circTLK1 acted as a sponge for miR‐513a‐3p, leading to the upregulation of KLF4, a key transcription factor for phenotypic switching. Targeting the circTLK1/miR‐513a‐3p/KLF4 axis may provide a potential therapeutic strategy for atherosclerosis.