Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium CurrentsNovelty and Significance
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Rationale: Ventricular arrhythmias often arise from the Purkinje–myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an induced Purkinje-like state characterized by prolonged action potential duration and expression of Purkinje-enriched genes.
Objective: To understand the mechanism by which canonical Notch signaling causes action potential prolongation.
Methods and Results: We find that endogenous Purkinje cells have reduced peak K+ current, Ito, and IK,slow when compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K+ current density, as well as the outward K+ current components Ito,f and IK,slow. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a and downregulation of K+ channel subunit genes that contribute to Ito,f and IK,slow. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K+ current amplitudes and mimics physiological hypertrophy. Notch-induced changes in K+ current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J (recombination signal binding protein for immunoglobulin kappa J region) binding and loss of active histone marks on K+ channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes.
Conclusions: In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology and may provide a novel target for arrhythmia drug design.
- action potential
- Brugada syndrome
- cellular reprogramming
- Notch receptors Purkinje cells
- Received September 2, 2016.
- Revision received September 27, 2016.
- Accepted September 30, 2016.
- © 2016 American Heart Association, Inc.