Logantha, Sunil Jit RJ, Stokke, Mathis K, Atkinson, Andrew J, Kharche, Sanjay R, Parveen, Sajida, Saeed, Yawer, Sjaastad, Ivar, Sejersted, Ole M and Dobrzynski, Halina
(2016)
Ca<SUP>2+</SUP>-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance.
FRONTIERS IN PHYSIOLOGY, 7 (JUN).
197-.
Abstract
<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 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 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 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.<h4>Conclusions</h4>Serca2 KO mice show a disrupted Ca(2+)-clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | sinus node, atrioventricular node, Ca2+-clock, SERCA2, heart failure, telemetry, heart rate, mathematical model |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 15 Jul 2020 09:15 |
| Last Modified: | 10 Oct 2023 19:19 |
| DOI: | 10.3389/fphys.2016.00197 |
| Open Access URL: | https://www.frontiersin.org/articles/10.3389/fphys... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3094044 |
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