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

Abstract

The voltage-gated cardiac Na⁺ channel (Na_v1.5), 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_v1.5 at lysine 1479 (K1479) and stimulates I_Na via lysine-deacetylation-mediated trafficking of Na_v1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Na_v1.5, decreases expression of Na_v1.5 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_v1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Na_v1.5, which promotes the trafficking of Na_v1.5 to the plasma membrane and stimulation of I_Na. As compared to wild-type Na_v1.5, Na_v1.5 with K1479 mutated to a nonacetylatable residue increases peak I_Na and is not regulated by Sirt1, whereas Na_v1.5 with K1479 mutated to mimic acetylation decreases I_Na. Na_v1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Na_v1.5, plays an essential part in the regulation of I_Na and cardiac electrical activity.