The effect of Sirt1 deficiency on Ca(2+) and Na(+) regulation in mouse ventricular myocytes

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca(2+) and Na(+) regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac‐specific Sirt1 knockout (Sirt1(−/−)). Sirt1(flox/flox) mice were served as control. Sirt1(−/−) mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca(2+) transient amplitudes and sarcoplasmic reticulum (SR) Ca(2+) stores, and increased SR Ca(2+) leak were shown in the Sirt1(−/−) mice. Electrophysiological measurements were performed using patch‐clamp method. While L‐type Ca(2+) current (I (Ca, L)) was smaller in Sirt1(−/−) myocytes, reverse‐mode Na(+)/Ca(2+) exchanger (NCX) current was larger compared with those in control myocytes. Late Na(+) current (I (Na, L)) was enhanced in the Sirt1(−/−) mice, alongside with elevated cytosolic Na(+) level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1(−/−) mice. Sirt1(−/−) cardiomyocytes showed down‐regulation of L‐type Ca(2+) channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), but up‐regulation of Ca(2+)/calmodulin‐dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca(2+) and Na(+) in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.