title: KChIP2 is a core transcriptional regulator of cardiac excitability.
abstract: Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and miR-34c, which subsequently targeted key depolarizing (INa) and repolarizing (Ito) currents altered in cardiac disease. Genetically maintaining KChIP2 expression or inhibiting miR-34 under pathologic conditions restored channel function and moreover, prevented the incidence of reentrant arrhythmias. This identifies the KChIP2/miR-34 axis as a central regulator in developing electrical dysfunction and reveals miR-34 as a therapeutic target for treating arrhythmogenesis in heart disease.
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.|Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States.
authors.forename: Drew M
authors.identifier: 0000-0002-8018-3913
authors.initials: DM
authors.lastname: Nassal
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Maleski
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Angelina
authors.initials: A
authors.lastname: Ramirez-Navarro
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic, Cleveland, United States.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Laurita
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States.|Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States.
authors.forename: Isabelle
authors.identifier: 0000-0002-1812-7267
authors.initials: I
authors.lastname: Deschênes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C496752:KCNIP2 protein, human; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; C522425:MIRN34 microRNA, human; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D012097:Repressor Proteins
keywords: INa; Ito; KChIP2; Kv4.3; Nav1.5; cell biology; heart failure (HF); human; human biology; medicine; rat