%0 Journal Article %1 Anto_2003_881 %A Antoons, Gudrun %A Heyen, Mark Ver %A Raeymaekers, Luc %A Vangheluwe, Peter %A Wuytack, Frank %A Sipido, Karin R %D 2003 %J Circ Res %K ATPases, ATPases; Animals; Blotting, Calcium, Calcium-Transporting Cardiac, Exchanger, Genotype; Heart Isoenzymes, Knockout; Membrane Mice, Mice; Mutation; Myocytes, Potentials, Reticulum Reticulum, Sarcoplasmic Sodium-Calcium Ventricles, Western; cytology/metabolism; genetics/metabolism; metabolism metabolism/pharmacokinetics; metabolism; physiology; %N 8 %P 881--887 %R 10.1161/01.RES.0000069032.81501.98 %T Ca2+ uptake by the sarcoplasmic reticulum in ventricular myocytes of the SERCA2b/b mouse is impaired at higher Ca2+ loads only. %U http://dx.doi.org/10.1161/01.RES.0000069032.81501.98 %V 92 %X 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.

@article{Anto_2003_881, abstract = {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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Antoons, Gudrun and Heyen, Mark Ver and Raeymaekers, Luc and Vangheluwe, Peter and Wuytack, Frank and Sipido, Karin R}, biburl = {https://www.bibsonomy.org/bibtex/2a7afb3b18015b1f1f70b1a877aa3b8b5/hake}, description = {The whole bibliography file I use.}, doi = {10.1161/01.RES.0000069032.81501.98}, file = {Anto_2003_881.pdf:Anto_2003_881.pdf:PDF}, institution = {Laboratory of Experimental Cardiology, University of Leuven, Leuven, Belgium.}, interhash = {f39b431397390f2a99c74e19ce099a13}, intrahash = {a7afb3b18015b1f1f70b1a877aa3b8b5}, journal = {Circ Res}, keywords = {ATPases, ATPases; Animals; Blotting, Calcium, Calcium-Transporting Cardiac, Exchanger, Genotype; Heart Isoenzymes, Knockout; Membrane Mice, Mice; Mutation; Myocytes, Potentials, Reticulum Reticulum, Sarcoplasmic Sodium-Calcium Ventricles, Western; cytology/metabolism; genetics/metabolism; metabolism metabolism/pharmacokinetics; metabolism; physiology;}, month = May, number = 8, pages = {881--887}, pdf = {Anto_2003_881.pdf}, pii = {01.RES.0000069032.81501.98}, pmid = {12663488}, timestamp = {2009-06-03T11:21:00.000+0200}, title = {Ca2+ uptake by the sarcoplasmic reticulum in ventricular myocytes of the SERCA2b/b mouse is impaired at higher Ca2+ loads only.}, url = {http://dx.doi.org/10.1161/01.RES.0000069032.81501.98}, volume = 92, year = 2003 }