KChIP2 is a core transcriptional regulator of cardiac excitability
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/17304 |
| _version_ | 1828204111831498752 |
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| author | Drew M Nassal Xiaoping Wan Haiyan Liu Danielle Maleski Angelina Ramirez-Navarro Christine S Moravec Eckhard Ficker Kenneth R Laurita Isabelle Deschênes |
| author_facet | Drew M Nassal Xiaoping Wan Haiyan Liu Danielle Maleski Angelina Ramirez-Navarro Christine S Moravec Eckhard Ficker Kenneth R Laurita Isabelle Deschênes |
| author_sort | Drew M Nassal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:17:07Z |
| format | Article |
| id | doaj.art-b6bb4391289341408afd11106adb8d98 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:17:07Z |
| publishDate | 2017-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b6bb4391289341408afd11106adb8d982022-12-22T03:33:24ZengeLife Sciences Publications LtdeLife2050-084X2017-03-01610.7554/eLife.17304KChIP2 is a core transcriptional regulator of cardiac excitabilityDrew M Nassal0https://orcid.org/0000-0002-8018-3913Xiaoping Wan1Haiyan Liu2Danielle Maleski3Angelina Ramirez-Navarro4Christine S Moravec5Eckhard Ficker6Kenneth R Laurita7Isabelle Deschênes8https://orcid.org/0000-0002-1812-7267Heart 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 StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesDepartment of Molecular Cardiology, Cleveland Clinic, Cleveland, United StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesHeart and Vascular Research Center, Department of Medicine, Case Western Reserve University, Cleveland, United StatesHeart 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 StatesArrhythmogenesis 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.https://elifesciences.org/articles/17304KChIP2Nav1.5Kv4.3INaItoheart failure (HF) |
| spellingShingle | Drew M Nassal Xiaoping Wan Haiyan Liu Danielle Maleski Angelina Ramirez-Navarro Christine S Moravec Eckhard Ficker Kenneth R Laurita Isabelle Deschênes KChIP2 is a core transcriptional regulator of cardiac excitability eLife KChIP2 Nav1.5 Kv4.3 INa Ito heart failure (HF) |
| title | KChIP2 is a core transcriptional regulator of cardiac excitability |
| title_full | KChIP2 is a core transcriptional regulator of cardiac excitability |
| title_fullStr | KChIP2 is a core transcriptional regulator of cardiac excitability |
| title_full_unstemmed | KChIP2 is a core transcriptional regulator of cardiac excitability |
| title_short | KChIP2 is a core transcriptional regulator of cardiac excitability |
| title_sort | kchip2 is a core transcriptional regulator of cardiac excitability |
| topic | KChIP2 Nav1.5 Kv4.3 INa Ito heart failure (HF) |
| url | https://elifesciences.org/articles/17304 |
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