Dataset Information

Ca(2+)-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance.

ABSTRACT:

Background

The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) pump is an important component of the Ca(2+)-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 Ca(2+)-clock with 2 ?M 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 Ca(2+)-clock. Mathematical modeling was used to dissect the effects of membrane- and Ca(2+)-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 Ca(2+)-clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.

SUBMITTER: Logantha SJ

PROVIDER: S-EPMC4889599 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ca(2+)-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance.

Logantha Sunil Jit R J SJ Stokke Mathis K MK Atkinson Andrew J AJ Kharche Sanjay R SR Parveen Sajida S Saeed Yawer Y Sjaastad Ivar I Sejersted Ole M OM Dobrzynski Halina H

Frontiers in physiology 20160602

<h4>Background</h4>The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) pump is an important component of the Ca(2+)-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.<h4>Methods and results</h4>In Serca2 KO mice, ventricular SERCA2a protein content measured by Western blotting was 75% (P < 0.05) lower than ...[more]

PMID: 27313537

Similar Datasets

Project description:Recent evidence supports the idea that robust and, importantly, FLEXIBLE automaticity of cardiac pacemaker cells is conferred by a coupled system of membrane ion currents (an "M-clock") and a sarcoplasmic reticulum (SR)-based Ca(2+) oscillator ("Ca(2+)clock") that generates spontaneous diastolic Ca(2+) releases. This study identified numerical models of a human biological pacemaker that features robust and flexible automaticity generated by a minimal set of electrogenic proteins and a Ca(2+)clock. Following the Occam's razor principle (principle of parsimony), M-clock components of unknown molecular origin were excluded from Maltsev-Lakatta pacemaker cell model and thirteen different model types of only 4 or 5 components were derived and explored by a parametric sensitivity analysis. The extended ranges of SR Ca(2+) pumping (i.e. Ca(2+)clock performance) and conductance of ion currents were sampled, yielding a large variety of parameter combination, i.e. specific model sets. We tested each set's ability to simulate autonomic modulation of human heart rate (minimum rate of 50 to 70bpm; maximum rate of 140 to 210bpm) in response to stimulation of cholinergic and β-adrenergic receptors. We found that only those models that include a Ca(2+)clock (including the minimal 4-parameter model "ICaL+IKr+INCX+Ca(2+)clock") were able to reproduce the full range of autonomic modulation. Inclusion of If or ICaT decreased the flexibility, but increased the robustness of the models (a relatively larger number of sets did not fail during testing). The new models comprised of components with clear molecular identity (i.e. lacking IbNa & Ist) portray a more realistic pacemaking: A smaller Na(+) influx is expected to demand less energy for Na(+) extrusion. The new large database of the reduced coupled-clock numerical models may serve as a useful tool for the design of biological pacemakers. It will also provide a conceptual basis for a general theory of robust, flexible, and energy-efficient pacemaking based on realistic components.

Dataset Information

Ca(2+)-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance.

Background

Methods and results

Conclusions

Publications

Ca(2+)-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance.

Similar Datasets

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