| First Author | Khandekar A | Year | 2016 |
| Journal | Circ Res | Volume | 119 |
| Issue | 12 | Pages | 1324-1338 |
| PubMed ID | 27697822 | Mgi Jnum | J:249973 |
| Mgi Id | MGI:6099846 | Doi | 10.1161/CIRCRESAHA.116.309877 |
| Citation | Khandekar A, et al. (2016) Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents. Circ Res 119(12):1324-1338 |
| abstractText | 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. |
