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Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel

Nature Medicine volume 23, pages 361–367 (2017)Cite this article

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Abstract

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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Figure 1: The interaction of Sirt1 with Nav1.5 and regulation of INa by Sirt1.
Figure 2: Regulation of Nav1.5 acetylation at K1479 by Sirt1.
Figure 3: Regulation of INa and trafficking of NaV1.5 via Sirt1-mediated deacetylation of K1479.
Figure 4: Bradyarrhythmias, tachyarrhythmias and conduction abnormalities related to increased K1479 acetylation of Nav1.5 in mice and humans.

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References

  1. Ruan, Y., Liu, N. & Priori, S.G. Sodium channel mutations and arrhythmias. Nat. Rev. Cardiol. 6, 337–348 (2009).

    Article  CAS  Google Scholar 

  2. Chen-Izu, Y. et al. Na+ channel function, regulation, structure, trafficking and sequestration. J. Physiol. (Lond.) 593, 1347–1360 (2015).

    Article  Google Scholar 

  3. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N. Engl. J. Med. 321, 406–412 (1989).

  4. Marionneau, C. & Abriel, H. Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications. J. Mol. Cell. Cardiol. 82, 36–47 (2015).

    Article  CAS  Google Scholar 

  5. Pei, Z., Xiao, Y., Meng, J., Hudmon, A. & Cummins, T.R. Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation. Nat. Commun. 7, 12035 (2016).

    Article  CAS  Google Scholar 

  6. Liu, M. et al. Cardiac Na+ current regulation by pyridine nucleotides. Circ. Res. 105, 737–745 (2009).

    Article  CAS  Google Scholar 

  7. Valdivia, C.R., Ueda, K., Ackerman, M.J. & Makielski, J.C. GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A. Am. J. Physiol. Heart Circ. Physiol. 297, H1446–H1452 (2009).

    Article  CAS  Google Scholar 

  8. Grant, A.O. et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J. Clin. Invest. 110, 1201–1209 (2002).

    Article  CAS  Google Scholar 

  9. Zhang, Z.S., Tranquillo, J., Neplioueva, V., Bursac, N. & Grant, A.O. Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease. Am. J. Physiol. Heart Circ. Physiol. 292, H399–H407 (2007).

    Article  CAS  Google Scholar 

  10. Hallaq, H. et al. Quantitation of protein kinase A-mediated trafficking of cardiac sodium channels in living cells. Cardiovasc. Res. 72, 250–261 (2006).

    Article  CAS  Google Scholar 

  11. Hallaq, H. et al. Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+ channels. Am. J. Physiol. Heart Circ. Physiol. 302, H782–H789 (2012).

    Article  CAS  Google Scholar 

  12. Royer, A. et al. Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis. Circulation 111, 1738–1746 (2005).

    Article  CAS  Google Scholar 

  13. van Bemmelen, M.X. et al. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ. Res. 95, 284–291 (2004).

    Article  CAS  Google Scholar 

  14. Bosch-Presegué, L. et al. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell 42, 210–223 (2011).

    Article  Google Scholar 

  15. Benson, D.W. et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J. Clin. Invest. 112, 1019–1028 (2003).

    Article  CAS  Google Scholar 

  16. Schott, J.J. et al. Cardiac conduction defects associate with mutations in SCN5A. Nat. Genet. 23, 20–21 (1999).

    Article  CAS  Google Scholar 

  17. Tan, H.L. et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 409, 1043–1047 (2001).

    Article  CAS  Google Scholar 

  18. Lei, M., Zhang, H., Grace, A.A. & Huang, C.L. SCN5A and sinoatrial node pacemaker function. Cardiovasc. Res. 74, 356–365 (2007).

    Article  CAS  Google Scholar 

  19. Papadatos, G.A. et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc. Natl. Acad. Sci. USA 99, 6210–6215 (2002).

    Article  CAS  Google Scholar 

  20. Probst, V. et al. Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease. J. Am. Coll. Cardiol. 41, 643–652 (2003).

    Article  CAS  Google Scholar 

  21. Yokokawa, M. et al. Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. Am. J. Cardiol. 100, 649–655 (2007).

    Article  CAS  Google Scholar 

  22. de Jong, S., van Veen, T.A., van Rijen, H.V. & de Bakker, J.M. Fibrosis and cardiac arrhythmias. J. Cardiovasc. Pharmacol. 57, 630–638 (2011).

    Article  CAS  Google Scholar 

  23. Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).

    Article  CAS  Google Scholar 

  24. Chandra, R., Starmer, C.F. & Grant, A.O. Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am. J. Physiol. 274, H1643–H1654 (1998).

    CAS  PubMed  Google Scholar 

  25. Schulze-Bahr, E. et al. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum. Mutat. 21, 651–652 (2003).

    Article  Google Scholar 

  26. Gao, G. et al. Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure. Circulation 124, 1124–1131 (2011).

    Article  CAS  Google Scholar 

  27. Herren, A.W., Bers, D.M. & Grandi, E. Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias. Am. J. Physiol. Heart Circ. Physiol. 305, H431–H445 (2013).

    Article  CAS  Google Scholar 

  28. Valdivia, C.R. et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J. Mol. Cell. Cardiol. 38, 475–483 (2005).

    Article  CAS  Google Scholar 

  29. McNair, W.P. et al. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J. Am. Coll. Cardiol. 57, 2160–2168 (2011).

    Article  Google Scholar 

  30. Zhao, Y. et al. Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol. Cell. Biol. 26, 2782–2790 (2006).

    Article  CAS  Google Scholar 

  31. Yoon, J.Y. et al. A novel Na+ channel agonist, dimethyl lithospermate B, slows Na+ current inactivation and increases action potential duration in isolated rat ventricular myocytes. Br. J. Pharmacol. 143, 765–773 (2004).

    Article  CAS  Google Scholar 

  32. Mattagajasingh, I. et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 104, 14855–14860 (2007).

    Article  CAS  Google Scholar 

  33. Mitchell, G.F., Jeron, A. & Koren, G. Measurement of heart rate and Q-T interval in the conscious mouse. Am. J. Physiol. 274, H747–H751 (1998).

    CAS  PubMed  Google Scholar 

  34. Petric, S. et al. In vivo electrophysiological characterization of TASK-1 deficient mice. Cell. Physiol. Biochem. 30, 523–537 (2012).

    Article  CAS  Google Scholar 

  35. Burgoyne, J.R. et al. Oxidation of HRas cysteine thiols by metabolic stress prevents palmitoylation in vivo and contributes to endothelial cell apoptosis. FASEB J. 26, 832–841 (2012).

    Article  CAS  Google Scholar 

  36. Dickey, D.M., Dries, D.L., Margulies, K.B. & Potter, L.R. Guanylyl cyclase (GC)-A and GC-B activities in ventricles and cardiomyocytes from failed and non-failed human hearts: GC-A is inactive in the failed cardiomyocyte. J. Mol. Cell. Cardiol. 52, 727–732 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

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Author notes

  1. Ajit Vikram, Christopher M Lewarchik and Jin-Young Yoon: These authors contributed equally to this work.

  2. Barry London and Kaikobad Irani: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Ajit Vikram, Jin-Young Yoon, Santosh Kumar, Gina M Morgan, Julia S Jacobs, Qiuxia Li, Young-Rae Kim, Modar Kassan, Jing Liu, Mohanad Gabani, Haider Mehdi, Xiaodong Zhu, Xiaoqun Guan, William Kutschke, Xiaoming Zhang, Ryan L Boudreau, Shengchuan Dai, Daniel S Matasic, Barry London & Kaikobad Irani

  2. University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Christopher M Lewarchik, Asma Naqvi & Ajay Kumar

  3. Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, South Korea

    Saet-Byel Jung

  4. Cardiovascular Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Kenneth B Margulies

  5. Vascular Biology Section, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts, USA

    Vikas Kumar & Markus M Bachschmid

  6. Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, and Heart and Vascular Center, University of Iowa, University of Iowa, Iowa City, Iowa, USA

    Kaikobad Irani

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Contributions

K.I. and B.L. designed and conceived the project. A.V., C.M.L., J.-Y.Y., A.N., S.K., G.M.M., J.S.J., Q.L., Y.-R.K., M.K., J.L., M.G., A.K., H.M., X. Zhu, X.G., W.K., X. Zhang, S.D., S.-B.J., V.K. and M.M.B. carried out experimental work, analyzed data and participated in data interpretation. R.L.B. and D.S.M. helped with data interpretation. K.B.M. provided critical human heart tissue and data set. K.I., B.L. and A.V. wrote the manuscript. K.I. and B.L. supervised the research and interpreted the data.

Corresponding authors

Correspondence to Barry London or Kaikobad Irani.

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Competing interests

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, JY. 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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