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 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.