Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses

TLDR

Circular RNAs are a subclass of non‑coding RNAs found in mammalian cells. The study aimed to investigate the role of circ‑Foxo3 in cellular senescence through in vitro and in vivo experiments. Using molecular and cellular biology techniques, the authors demonstrated that circ‑Foxo3 is highly expressed in aged heart tissue and correlates with senescence markers. Ectopic circ‑Foxo3 exacerbated doxorubicin‑induced cardiomyopathy and promoted senescence, while silencing circ‑Foxo3 alleviated cardiomyopathy, reduced fibroblast senescence, and prevented cytoplasmic sequestration of ID‑1, E2F1, FAK, and HIF1α, thereby restoring their anti‑senescence and anti‑stress activities.

Abstract

Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches.Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α.We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.