Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents

Aditi Khandekar, Steven Springer, Wei Wang, Stephanie Hicks, Carla Weinheimer, Ramon Diaz-Trelles, Jeanne M. Nerbonne, Stacey Rentschler

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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, I to, and I K,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 I to,f and I K, 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 I to,f and I K,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.

Original languageEnglish
Pages (from-to)1324-1338
Number of pages15
JournalCirculation research
Volume119
Issue number12
DOIs
StatePublished - Dec 9 2016

Keywords

  • Brugada syndrome
  • Notch receptors Purkinje cells
  • action potential
  • cardiomyopathies
  • cellular reprogramming
  • electrophysiology

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