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The voltage-gated cardiac Na + channel (Na v 1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na + current (I Na ) 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 v 1.5 at lysine 1479 (K1479) and stimulates I Na via lysine-deacetylation-mediated trafficking of Na v 1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Na v 1.5, decreases expression of Na v 1.5 on the cardiomyocyte membrane, reduces I Na 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 v 1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Na v 1.5, which promotes the trafficking of Na v 1.5 to the plasma membrane and stimulation of I Na . As compared to wild-type Na v 1.5, Na v 1.5 with K1479 mutated to a nonacetylatable residue increases peak I Na and is not regulated by Sirt1, whereas Na v 1.5 with K1479 mutated to mimic acetylation decreases I Na . Na v 1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Na v 1.5, plays an essential part in the regulation of I Na and cardiac electrical activity.

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