Journal
EUROPEAN HEART JOURNAL
Volume 38, Issue 18, Pages 1402-1412Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehw001
Keywords
Circular RNA; Heart senescence; Foxo3; Stress response
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [227937-2012]
- Heart and Stroke Foundation of Ontario [CI 7418]
- Breast Cancer Foundation of Ontario
- China Scholarship Council
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Aims 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. Methods and results 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 HIF1 alpha. Conclusion We conclude that ID-1, E2F1, FAK, and HIF1 alpha 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.
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