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
Xiaoping Wan
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
Haiyan Liu
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
Danielle Maleski
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
Angelina Ramirez-Navarro
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
Christine S Moravec
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, United States
Eckhard Ficker
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
Kenneth R Laurita
Heart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United States
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
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.
