title: A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223.
abstract: Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown.
  
  
  
  Here we show that a circular RNA (circRNA), which we term heart-related circRNA (HRCR), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses.
  
  
  
  These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China wangk696@163.com peifengliqd@163.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Medicine, Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100730, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Long
authors.affiliation: Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin 541004, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Jian-Xun
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Cui-Yun
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Lu-Yu
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Sun
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Man
authors.initials: M
authors.lastname: Wang
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Yan-Han
authors.initials: YH
authors.lastname: Dong
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China wangk696@163.com peifengliqd@163.com.
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D006332:Cardiomegaly; D006333:Heart Failure; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs; D032383:Myocytes, Cardiac
chemical_list: D035683:MicroRNAs
keywords: Cardiac hypertrophy; Circular RNA; HRCR; Heart failure