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 and Na regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1 ). Sirt1 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 transient amplitudes and sarcoplasmic reticulum (SR) Ca stores, and increased SR Ca leak were shown in the Sirt1 mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca current (I ) was smaller in Sirt1 myocytes, reverse-mode Na /Ca exchanger (NCX) current was larger compared with those in control myocytes. Late Na current (I ) 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 channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca ATPase 2a (SERCA2a), but up-regulation of Ca /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca and Na in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.