Reduced SERCA2 abundance decreases the propensity for Ca2+ wave development in ventricular myocytes.
OBJECTIVE
To describe the overall role of reduced sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) for Ca(2+) wave development.


RESULTS
SERCA2 knockout [Serca2(flox/flox) Tg(alphaMHC-MerCreMer); KO] mice allowing inducible cardiomyocyte-specific disruption of the Serca2 gene in adult mice were compared with Serca(flox/flox) (FF) control mice. Six days after Serca2 gene disruption, SERCA2 protein abundance was reduced by 53% in KO compared with FF, whereas SERCA2 activity in field-stimulated, Fluo-5F AM-loaded cells was reduced by 42%. Baseline Ca(2+) content of the sarcoplasmic reticulum (SR) and Ca(2+) transient amplitude and rate constant of decay measured in whole-cell voltage-clamped cells were decreased in KO to 75, 81, and 69% of FF values. Ca(2+) waves developed in only 31% of KO cardiomyocytes compared with 57% of FF when external Ca(2+) was raised (10 mM), although SR Ca(2+) content needed for waves to develop was 79% of FF values. In addition, waves propagated at a 15% lower velocity in KO cells. Ventricular extrasystoles (VES) occurred with lower frequency in SERCA2 KO mice (KO: 3 +/- 1 VES/h vs. FF: 8 +/- 1 VES/h) (P < 0.05 for all results).


CONCLUSIONS
Reduced SERCA2 abundance resulted in decreased amplitude and decay rate of Ca(2+) transients, reduced SR Ca(2+) content, and decreased propensity for Ca(2+) wave development.
Stokke
Mathis K
MK
Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Kirkeveien 166, N-0407 Oslo, Norway. m.k.stokke@medisin.uio.no
Hougen
Karina
K
Sjaastad
Ivar
I
Louch
William E
WE
Briston
Sarah J
SJ
Enger
Ulla H
UH
Andersson
Kristin B
KB
Christensen
Geir
G
Eisner
David A
DA
Sejersted
Ole M
OM
Trafford
Andrew W
AW
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism*; D018879:Ventricular Premature Complexes / Q000378:metabolism / Q000503:physiopathology*
D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium