Abstract
Background: The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) pump is an important component of the Ca2+-clock pacemaker mechanism that provides robustness and flexibility to sinus node pacemaking. We have developed transgenic mice with reduced cardiac SERCA2 abundance (Serca2 KO) as a model for investigating SERCA2's role in sinus node pacemaking.Methods and Results: In Serca2 KO mice, ventricular SERCA2a protein content measured by Western blotting was 75% (P < 0.05) lower than that in control mice (Serca2 FF) tissue. Immunofluorescent labeling of SERCA2a in ventricular, atrial, sinus node periphery and center tissue sections revealed 46, 45, 55, and 34% (all P < 0.05 vs. Serca2 FF) lower labeling, respectively and a mosaic pattern of expression. With telemetric ECG surveillance, we observed no difference in basal heart rate, but the PR-interval was prolonged in Serca2 KO mice: 49 ± 1 vs. 40 ± 1 ms (P < 0.001) in Serca2 FF. During exercise, heart rate in Serca2 KO mice was elevated to 667 ± 22 bpm, considerably less than 780 ± 17 bpm (P < 0.01) in Serca2 FF. In isolated sinus node preparations, 2 mM Cs+ caused bradycardia that was equally pronounced in Serca2 KO and Serca2 FF (32 ± 4% vs. 29 ± 5%), indicating no change in the pacemaker current, If. Disabling the Ca2+-clock with 2 μM ryanodine induced bradycardia that was less pronounced in Serca2 KO preparations (9 ± 1% vs. 20 ± 3% in Serca2 FF; P < 0.05), suggesting a disrupted Ca2+-clock. Mathematical modeling was used to dissect the effects of membrane- and Ca2+-clock components on Serca2 KO mouse heart rate and sinus node action potential. Computer modeling predicted a slowing of heart rate with SERCA2 downregulation and the heart rate slowing was pronounced at >70% reduction in SERCA2 activity.Conclusions: Serca2 KO mice show a disrupted Ca2+-clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.
Highlights
The sinus node is the dominant pacemaker of the heart, aptly placed in the roof of the right atrium
With telemetric ECG surveillance, we observed no difference in basal heart rate, but the PR-interval was prolonged in Serca2 KO mice: 49 ± 1 vs. 40 ± 1 ms (P < 0.001) in Serca2 FF
In isolated sinus node preparations, 2 mM Cs+ caused bradycardia that was pronounced in Serca2 KO and Serca2 FF (32 ± 4% vs. 29 ± 5%), indicating no change in the pacemaker current, If
Summary
The sinus node is the dominant pacemaker of the heart, aptly placed in the roof of the right atrium. The diastolic depolarization results from the synergistic interaction between an ensemble of surface membrane ion channel currents and intracellular Ca2+ release signals Together, they regulate the rate and rhythm of the spontaneous action potentials in the sinus node (Figure 1; Dobrzynski et al, 2007; Lakatta et al, 2010). The voltage- and time-dependent gating of the surface membrane channels works in a cyclic fashion (the membrane voltage-clock) and underlies the early phase of the diastolic depolarization This phase involves a voltage-dependent deactivation of outward currents and activation of inward currents (Dobrzynski et al, 2013). The hyperpolarization-activated cyclic nucleotide-gated (HCN) or funny current (If) is the main inward current, and a vital component of the voltage-clock and essential to pacemaking in the sinus node. We have developed transgenic mice with reduced cardiac SERCA2 abundance (Serca KO) as a model for investigating SERCA2’s role in sinus node pacemaking
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