Ca2+ uptake by the sarcoplasmic reticulum in ventricular myocytes of the SERCA2b/b mouse is impaired at higher Ca2+ loads only.
SERCA2a is the cardiac-specific isoform of Ca2+-ATPase of the sarcoplasmic reticulum (SR). A reduction of SERCA2a has been implicated in the contractile dysfunction of heart failure, and partial knockout of the SERCA2 gene (Atp2a2+/- mice) reiterated many of the features of heart failure. Yet, mice with a mutation of Atp2a2, resulting in full suppression of the SERCA2a isoform and expression of the SERCA2b isoform only (SERCA2b/b), showed only moderate functional impairment, despite a reduction by 40% of the SERCA2 protein levels. We examined in more detail the Ca2+ handling in isolated cardiac myocytes from SERCA2b/b. At 0.25 Hz stimulation, the amplitude of the [Ca2+]i transients, SR Ca2+ content, diastolic [Ca2+]i, and density of ICaL were comparable between WT and SERCA2b/b. However, the decline of [Ca2+]i was slower (t1/2 154+/-7 versus 131+/-5 ms; P<0.05). Reducing the amplitude of the [Ca2+]i transient (eg, SR depletion), removed the differences in [Ca2+]i decline. In contrast, increasing the Ca2+ load revealed pronounced reduction of SR Ca2+ uptake at high [Ca2+]i. There was no increase in Na+-Ca2+ exchange protein or function. Theoretical modeling indicated that in the SERCA2b/b mouse, the higher Ca2+ affinity of SERCA2b partially compensates for the 40% reduction of SERCA expression. The lack of SR depletion in the SERCA2b/b may also be related to the absence of upregulation of Na+-Ca2+ exchange. We conclude that for SERCA isoforms with increased affinity for Ca2+, a reduced expression level is better tolerated as Ca2+ uptake and storage are impaired only at higher Ca2+ loads.
Antoons
Gudrun
G
Laboratory of Experimental Cardiology, University of Leuven, Leuven, Belgium.
Ver Heyen
Mark
M
Raeymaekers
Luc
L
Vangheluwe
Peter
P
Wuytack
Frank
F
Sipido
Karin R
KR
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D007527:Isoenzymes; D019831:Sodium-Calcium Exchanger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium