title: Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels.
abstract: BACKGROUND
  Cold-inducible RNA-binding protein (CIRP) is constitutively expressed at low levels across various tissues. It is rapidly upregulated by multiple stresses, underlying a general role for CIRP in organic adaptations to pathophysiological conditions. However, the role of CIRP in the heart remains unclear.
  
  
  OBJECTIVE
  To examine the biofunctions of CIRP in the mammalian heart.
  
  
  RESULTS
  Rats with targeted disruption of Cirp were generated using the TALEN (transcription activator-like effector nucleases)-based genome editing technique. The Cirp-knockout rats had structurally and functionally normal hearts. Resting ECG recordings revealed a short rate-corrected QT (QTc) interval in Cirp-null rats without any abnormalities in PR interval, RR interval or QRS waves as compared to wild-type animals. The shortened QTc interval from Cirp ablation was tightly linked to an abbreviated action potential duration in cardiac myocytes, which was attributable to increased transient outward potassium current (Ito). Furthermore, our findings uncovered that CIRP protein selectively bonded to KCND2 and KCND3 mRNAs encoding the functional α-subunits of Ito channel proteins. CIRP deficiency did not change the transcriptional activity of KCND2 or KCND3, but it facilitated their translation. Cirp knockout had no effect on the functional expression of ion channels other than Ito channels.
  
  
  CONCLUSIONS
  CIRP modulates cardiac repolarization by negatively adjusting the expression and function of Ito channels. Our study may open a window to decipher the potential function of RNA-binding proteins in bioelectric activity.
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Duanyang
authors.initials: D
authors.lastname: Xie
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Fei
authors.initials: F
authors.lastname: Lv
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Li
authors.initials: L
authors.lastname: Geng
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.).
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: From the Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine (J.L., D.X., J.H., F.L., D.S., Y.L., L.L., L.G., Y.W., D.L., Y.-H.C.); Institute of Medical Genetics, Tongji University (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine (J.L., D.S., Y.L., L.L., D.L., Y.-H.C.); Department of Cardiology, East Hospital, Tongji University School of Medicine (D.X., J.H., F.L., L.G., Y.W., Y.-H.C.) and Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, China (Y.-H.C.). yihanchen@tongji.edu.cn.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D057773:Cold Shock Proteins and Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006339:Heart Rate; D015640:Ion Channel Gating; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055647:Rats, Transgenic; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C585827:Cirbp protein, rat; D057773:Cold Shock Proteins and Peptides; C497020:Kcnd2 protein, rat; C497023:Kcnd3 protein, rat; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051672:Shal Potassium Channels
keywords: action potential; cardiac; cold shock proteins; ion channels; myocytes; repolarization