title: Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel.
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 phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INavia 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 INaand 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 INaand 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 INaand cardiac electrical activity.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Ajit
authors.identifier: http://orcid.org/0000-0003-3724-3842
authors.initials: A
authors.lastname: Vikram
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Lewarchik
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Yoon
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Asma
authors.initials: A
authors.lastname: Naqvi
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Morgan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Jacobs
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Mohanad
authors.initials: M
authors.lastname: Gabani
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Haider
authors.initials: H
authors.lastname: Mehdi
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Boudreau
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Shengchuan
authors.initials: S
authors.lastname: Dai
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Matasic
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, South Korea.
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Vascular Biology Section, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Vascular Biology Section, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Markus M
authors.identifier: http://orcid.org/0000-0002-0748-5528
authors.initials: MM
authors.lastname: Bachschmid
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: London
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.|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.
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
mesh_terms: D000107:Acetylation; D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D009202:Cardiomyopathies / Q000378:metabolism*; D004452:Echocardiography; D004562:Electrocardiography; D057809:HEK293 Cells; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1