KChIP2 is a core transcriptional regulator of cardiac excitability
| Autor: | Drew M Nassal, Xiaoping Wan, Haiyan Liu, Danielle Maleski, Angelina Ramirez-Navarro, Christine S Moravec, Eckhard Ficker, Kenneth R Laurita, Isabelle Deschênes |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | eLife, Vol 6 (2017) |
| Druh dokumentu: | article |
| ISSN: | 2050-084X 43912893 |
| DOI: | 10.7554/eLife.17304 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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