The voltage-gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes1. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Nav1.5, decreases expression of Nav1.5 on the cardiomyocyte membrane, reduces INa and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirt1-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Nav1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Nav1.5, which promotes the trafficking of Nav1.5 to the plasma membrane and stimulation of INa. As compared to wild-type Nav1.5, Nav1.5 with K1479 mutated to a nonacetylatable residue increases peak INa and is not regulated by Sirt1, whereas Nav1.5 with K1479 mutated to mimic acetylation decreases INa. Nav1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Nav1.5, plays an essential part in the regulation of INa and cardiac electrical activity.
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This work was supported by NIH grant HL115955 to K.I. and B.L., and University of Iowa Endowed Professorship to K.I. M.K. was supported by a Cardiovascular Institutional Research Fellowship (T32 HL007121, PI: F. Abboud). Q.L. was supported by the Training Program in Hematology: Molecular & Cell Biology of Blood Cells (T32 HL007344, PI: S. Lentz). Procurement of human heart tissue was enabled by NIH grant HL105993 to K.B.M. Proteomics studies were supported by NIH grants HL068758 and HL104017 (PI: R.A. Cohen) and DK103750 to M.M.B. We acknowledge NIH support for services that we received under contract HHSN268201000031 (PI: C. Costello). We acknowledge J. Lee at the Dana-Farber Molecular Biology Core Facility for his support with the MALDI and Orbitrap MS instruments. Cardiomyocyte imaging data were acquired at the University of Iowa Central Microscopy Research Facility, with NIH 1S10RR02543901 funding for the shared Zeiss LSM 710 Confocal Microscope. Mouse echocardiograms were made possible with the NIH shared instrument grant 1S10ODO019941. We thank S. Dudley for the Nav1.5-expressing cell line, T. Kouzarides for the Sirt1 constructs and D. Roden for the Scn5a+/− mice.
K.I. and B.L. have submitted a provisional patent filing on the use of Sirt1 activators for treatment of arrhythmias. The other authors declare that they have no competing interests.
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Vikram, A., Lewarchik, C., Yoon, J. et al. Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel. Nat Med 23, 361–367 (2017). https://doi.org/10.1038/nm.4284
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