Serum-derived exosomal circENC1 inhibits SMC phenotypic switching to stabilize atherosclerotic plaques by interacting with miR-513a-5p and inhibiting MYH9 degradation 

Abstract

Introduction: The function of serum-derived exosomes (serum-exos) that suppress smooth muscle cell (SMC) phenotypic switching-related genes in plaque stabilization is unclear. We aimed to determine the functional role of serum-exos, which are pivotal molecular regulators, in plaque stabilization and the underlying mechanism. Methods and results RNA sequencing and bioinformatic analyses of human serum-exos were used to identify circENC1, which is involved in SMC phenotypic switching and plaque stabilization. qRT‒PCR assays further confirmed that the circENC1 level was substantially lower in the unstable plaque (UP)-exo group than in the stable plaque (SP)-exo group. In mice treated with serum-exos from patients with SPs, the expression of the SMC contractile phenotype indicators ACTA2 and SM22 and the plaque stability increased. In contrast, in the group treated with serum-exos from patients with UPs, CD68 expression and the vulnerability index were increased. Moreover, circENC1 expression was negatively correlated with the plaque vulnerability index in the UP-exo group and the sham group. Mechanistically, single-cell analysis, chromatin isolation by RNA purification (ChIRP) and dual-luciferase reporter assays indicated that circENC1 suppressed SMC phenotypic switching by inhibiting the degradation of MYH9 and acting as a miR-513a-5p sponge to release MYOCD. Conclusion Serum exosomal circENC1 inhibits SMC phenotypic switching to stabilize plaques by binding to miR-513a-5p and inhibiting MYH9 degradation, indicating that this molecule may play an important role in the clinical diagnosis and treatment of atherosclerotic plaques.