Key result
Cardiac Sirt1 deficiency reduces Ca2+ transient amplitudes ~26% and promotes arrhythmogenesis.
Why the study?
This study tested the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis.
Does cardiac-specific Sirt1 deficiency alter cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis in mice?
Does cardiac-specific Sirt1 deficiency alter cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis in mice?
Cardiac-specific Sirt1 deficiency in mice impairs intracellular Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis.
Does not inform clinical practice; hypothesis-generating for Sirt1 in cardiomyocyte ion regulation and arrhythmogenesis.
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.
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Yang et al. (2020) studied Cardiac dysfunction and arrhythmogenesis. Cardiac-specific Sirt1 deficiency vs. Sirt1 flox/flox control mice was evaluated on Steady-state Ca2+ transient amplitudes (p=<0.005). Cardiac-specific Sirt1 deficiency in mice impaired intracellular Ca2+ and Na+ regulation, reducing steady-state Ca2+ transient amplitudes by 26% and provoking cardiac dysfunction and arrhythmogenesis.
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