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


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 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.


CONCLUSIONS
Serca2 KO mice show a disrupted Ca(2+)-clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Sunil Jit R J
SJ
Logantha
Institute for Experimental Medical Research, Oslo University Hospital and University of OsloOslo, Norway; Center for Heart Failure Research, University of OsloOslo, Norway; Clinic for Internal Medicine, Lovisenberg Deaconess Hospital ASOslo, Norway.
Mathis K
MK
Stokke
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Andrew J
AJ
Atkinson
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Sanjay R
SR
Kharche
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Sajida
S
Parveen
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Yawer
Y
Saeed
Institute for Experimental Medical Research, Oslo University Hospital and University of OsloOslo, Norway; Center for Heart Failure Research, University of OsloOslo, Norway.
Ivar
I
Sjaastad
Institute for Experimental Medical Research, Oslo University Hospital and University of OsloOslo, Norway; Center for Heart Failure Research, University of OsloOslo, Norway.
Ole M
OM
Sejersted
Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
Halina
H
Dobrzynski
Ca2+-clock; SERCA2; atrioventricular node; heart failure; heart rate; mathematical model; sinus node; telemetry