Reduced SERCA2 abundance decreases the propensity for Ca2+ wave development in ventricular myocytes

Abstract

Aims: To describe the overall role of reduced sarcoplasmic reticulum Ca2+ ATPase (SERCA2) for Ca2+ wave development. Methods and results: SERCA2 knockout [Serca2flox/flox Tg(αMHC- MerCreMer); KO] mice allowing inducible cardiomyocyte-specific disruption of the Serca2 gene in adult mice were compared with Sercaflox/flox (FF) control mice. Six days after Serca2 gene disruption, SERCA2 protein abundance was reduced by 53% in KO compared with FF, whereas SERCA2 activity in field-stimulated, Fluo-5F AM-loaded cells was reduced by 42%. Baseline Ca 2+ content of the sarcoplasmic reticulum (SR) and Ca2+ transient amplitude and rate constant of decay measured in whole-cell voltage-clamped cells were decreased in KO to 75, 81, and 69% of FF values. Ca2+ waves developed in only 31% of KO cardiomyocytes compared with 57% of FF when external Ca2+ was raised (10 mM), although SR Ca 2+ content needed for waves to develop was 79% of FF values. In addition, waves propagated at a 15% lower velocity in KO cells. Ventricular extrasystoles (VES) occurred with lower frequency in SERCA2 KO mice (KO: 3 ± 1 VES/h vs. FF: 8 ± 1 VES/h) (P < 0.05 for all results). Conclusion: Reduced SERCA2 abundance resulted in decreased amplitude and decay rate of Ca2+ transients, reduced SR Ca2+ content, and decreased propensity for Ca2+ wave development. © The Author 2009.