Abstract 19788: SIRT1 as a Novel Regulator of Cardiac Na+ Channels: A Potential Therapeutic Target for Arrhythmia
Introduction: Ion channel disorders are responsible for inherited and acquired forms of heart disease. Mutations in the cardiac voltage-gated Na+ channel (Nav1.5) cause inherited long QT and Brugada syndromes, and changes in Nav1.5 expression and function can promote arrhythmia susceptibility. In spite of the critical role of Nav1.5 in cardiac excitation-contraction coupling, the identity and role(s) of Nav1.5 modifying genes in both inherited and acquired arrhythmias are less well established.
Aim of studies: We previously showed in both heterologous expression systems and in rat neonatal cardiac myocytes that SIRTUIN1 (SIRT1), an NAD+-dependent lysine deacetylase, increases Na+ current (INa) by binding to, deacetylating, and promoting membrane localization of Nav1.5. Here, we tested the hypothesis that SIRT1 increases INa in vivo by modifying Nav1.5 acetylation.
Methods: We engineered cardiac-specific Sirt1-knockout mice (cSirt1-/-: Sirt1flox/flox x αMHC-Cre), recorded INa from isolated ventricular myocytes by whole cell patch clamp, detected Nav1.5 acetylation by Western blot and immunostaining, and recorded electrocardiograms (ECGs) in anesthetized and telemetry in ambulatory mice.
Results: INa in cSirt1-/- ventricular myocytes was decreased by 39 ± 6 % compared to the littermate controls (n=8 each, p=0.02; Figure). Nav1.5-acetylation was increased in cSirt1-/- mice by Western blot and immunostaining. ECG recordings from 6 month-old cSirt1-/- mice showed QRS prolongation, and ambulatory telemetry showed high degree heart block and runs of ventricular tachycardia. Sudden death was prominent in cSirt1-/- mice despite only mild depression of left ventricular function.
Conclusion: Cardiac-specific disruption of Sirt1 in mice leads to arrhythmias in vivo by decreasing INa, most likely through changes in Nav1.5 trafficking. Increasing SIRT1 expression and/or activity may provide a mechanism for preventing and/or treating arrhythmias.
Author Disclosures: J. Yoon: None. C. Lewarchik: None. S. Dai: None. H. Mehdi: None. X. Zhu: None. G.M. Morgan: None. Y. Kim: None. A. Vikram: None. A. Naqvi: None. K. Irani: None. B. London: None.
- © 2014 by American Heart Association, Inc.