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

The voltage-gated cardiac Na+ channel (Na(v)1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (/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(1). Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Na(v)1.5 at lysine 1479 (K1479) and stimulates /Na via lysine-deacetylation-mediated trafficking of Nav1.5 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 /Na and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirtl-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Na(v)1.5. Increased Sirtl 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 /Na. As compared to wild-type Na(v)1.5, Na(v)1.5 with K1479 mutated to a nonacetylatable residue increases peak /Na and is not regulated by Sirtl, whereas Na(v)1.5 with K1479 mutated to mimic acetylation decreases I. 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 /Na and cardiac electrical activity.