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Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel
Journal article   Peer reviewed

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

Ajit Vikram, Christopher M Lewarchik, Jin-Young Yoon, Asma Naqvi, Santosh Kumar, Gina M Morgan, Julia S Jacobs, Qiuxia Li, Young-Rae Kim, Modar Kassan, …
Nature medicine, Vol.23(3), pp.361-367
03/2017
DOI: 10.1038/nm.4284
PMCID: PMC6218171
PMID: 28191886

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Abstract

The voltage-gated cardiac Na channel (Na 1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na current (I ) 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 Na 1.5 at lysine 1479 (K1479) and stimulates I via lysine-deacetylation-mediated trafficking of Na 1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Na 1.5, decreases expression of Na 1.5 on the cardiomyocyte membrane, reduces I 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 Na 1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Na 1.5, which promotes the trafficking of Na 1.5 to the plasma membrane and stimulation of I . As compared to wild-type Na 1.5, Na 1.5 with K1479 mutated to a nonacetylatable residue increases peak I and is not regulated by Sirt1, whereas Na 1.5 with K1479 mutated to mimic acetylation decreases I . Na 1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Na 1.5, plays an essential part in the regulation of I and cardiac electrical activity.
 Immunoprecipitation Mass Spectrometry Heart - physiopathology Sirtuin 1 - metabolism Myocytes, Cardiac Echocardiography Humans Rats Immunoblotting NAV1.5 Voltage-Gated Sodium Channel - metabolism Sirtuin 1 - genetics Heart - diagnostic imaging Mice, Knockout Action Potentials Patch-Clamp Techniques Animals Membrane Potentials Cardiomyopathies - metabolism Myocardium - metabolism HEK293 Cells Electrocardiography Mice Acetylation Arrhythmias, Cardiac - genetics

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