Abstract
Abstract 9671: SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability
Circulation (New York, N.Y.), Vol.140(Suppl_1 Suppl 1), pp.A9671-A9671
11/19/2019
DOI: 10.1161/circ.140.suppl_1.9671
Abstract
IntroductionSUMOylation, the addition of a Small Ubiquitin-like MOdifier (SUMO), is a post-translational modification that modulates an array of proteins in various cellular processes. Cardiac Na channel NaV1.5, encoded by SCN5A, critically controls cell excitability, and altered channel gating has been implicated in both inherited and acquired arrhythmias.HypothesisWe tested whether SUMOylation of the cardiac sodium channel NaV1.5 modifies the inward Na current (INa) and influences cardiac electrical activity.MethodsSUMOylation of NaV1.5 by SUMO1 was detected by immunoprecipitation and immunoblotting. The effects of SUMOylation/de-SUMOylation on the amplitude and properties of INa in HEK293 cells transiently transfected with wild type (WT) and mutant (K442R) NaV1.5 and in neonatal rat cardiac myocytes (NRCMs) were measured using whole-cell and inside-out patch clamp. The role of SUMOylation in vivo was studied using electrocardiograms (EKGs) and ambulatory telemetry on Scn5a heterozygous knockout (SCN5A) mice treated with adeno-associated virus overexpression of the de-SUMOylating protein SENP2 (AAV-SENP2) or the SUMOylation inhibitor anacardic acid.ResultsNaV1.5 in HEK cells, NRCMs and human heart samples is SUMOylated by SUMO1. Overexpression or direct application of SUMO1 induced hyperSUMOylation of NaV1.5 at K442 and increased the amplitude of INa in NRCMs and in HEK cells overexpressing WT but not K442R-Nav1.5 (Fig 1A). Forcing hypoSUMOylation in SCN5A mice by AAV9-SENP2 overexpression or by treatment with anacardic acid led to decreased INa in cardiac myocytes (Fig 1B), QRS prolongation (Fig 1C), heart block and ventricular arrhythmias.ConclusionSUMO1-mediated SUMOylation of Nav1.5 at K442 increases INa, while deSUMOylation produces conduction defects and arrhythmias in mice. SUMOylation of Nav1.5 may modify arrhythmic risk in disease states and represents a potential target for pharmacological manipulation.
Details
- Title: Subtitle
- Abstract 9671: SUMOylation of the Cardiac Sodium Channel NaV1.5 Modifies Inward Current and Cardiac Excitability
- Creators
- Jin-Young Yoon - University of IowaAlex Greiner - Div of Cardiovascular Medicine, Dept of Internal Medicine, Univ of Iowa Carver College of Medicine, Iowa City, IAJulia Jacobs - Div of Cardiovascular Medicine, Dept of Internal Medicine, Univ of Iowa Carver College of Medicine, Iowa City, IAWilliam Kutschke - University of IowaYoung-Rae Kim - University of IowaDaniel Matasic - University of IowaGina Morgan - Div of Cardiovascular Medicine, Dept of Internal Medicine, Univ of Iowa Carver College of Medicine, Iowa City, IAHaider Mehdi - University of IowaKaikobad Irani - University of IowaBarry London - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.140(Suppl_1 Suppl 1), pp.A9671-A9671
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- DOI
- 10.1161/circ.140.suppl_1.9671
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/19/2019
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Radiation Oncology
- Record Identifier
- 9984303005902771
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