KChIP2 is a core transcriptional regulator of cardiac excitability

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Authors

External Institution(s)

  • Case Western Reserve University

Details

Original languageEnglish (US)
Article numbere17304
JournaleLife
Volume6
StatusPublished - Mar 6 2017
Peer-reviewedYes

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.

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Nassal, DM, Wan, X, Liu, H, Maleski, D, Ramirez-Navarro, A, Moravec, CS, Ficker, E, Laurita, KR & Deschênes, I 2017, 'KChIP2 is a core transcriptional regulator of cardiac excitability', eLife, vol. 6, e17304. https://doi.org/10.7554/eLife.17304.001