AUTHOR=Logantha Sunil Jit R. J. , Stokke Mathis K. , Atkinson Andrew J. , Kharche Sanjay R. , Parveen Sajida , Saeed Yawer , Sjaastad Ivar , Sejersted Ole M. , Dobrzynski Halina TITLE=Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance JOURNAL=Frontiers in Physiology VOLUME=7 YEAR=2016 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2016.00197 DOI=10.3389/fphys.2016.00197 ISSN=1664-042X 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, I_f. 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.