title: Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses.
abstract: OBJECTIVE
  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.
  
  
  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 HIF1α.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, S-Wing Research Building, 2075 Bayview Ave, Toronto M4N 3M5, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Weining
authors.initials: W
authors.lastname: Yang
authors.affiliation: 2nd Department of Cardiac Surgery, The First Hospital, Sun Yet-Sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 2nd Department of Cardiac Surgery, The First Hospital, Sun Yet-Sen University, Guangzhou, China.
authors.forename: Zhong-Kai
authors.initials: ZK
authors.lastname: Wu
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors.forename: Francis Stuart
authors.initials: FS
authors.lastname: Foster
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, S-Wing Research Building, 2075 Bayview Ave, Toronto M4N 3M5, Canada.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, S-Wing Research Building, 2075 Bayview Ave, Toronto M4N 3M5, Canada.|State Key Laboratory of Applied Microbiology Southern China (The Ministry-Province Joint Development), Guangdong Institute of Microbiology, Guangzhou 510070, PR China.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, S-Wing Research Building, 2075 Bayview Ave, Toronto M4N 3M5, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D004317:Doxorubicin / Q000633:toxicity; D050687:E2F1 Transcription Factor / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D000071316:Forkhead Box Protein O3 / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D051379:Mice; D021381:Protein Transport; D012313:RNA / Q000502:physiology*; D000079962:RNA, Circular; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D000079962:RNA, Circular; D012313:RNA; D004317:Doxorubicin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
keywords: Circular RNA; Foxo3; Heart senescence; Stress response