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Title: Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca²⁺ homeostasis but not Ca²⁺-dependent hypertrophic signaling
Authors: Louch, William E
Vangheluwe, Peter ×
Bito, Virginie
Raeymaekers, Luc
Wuytack, Frank
Sipido, Karin #
Issue Date: Jun-2012
Series Title: American Journal of Physiology. Heart and Circulatory Physiology vol:302 issue:12 pages:H2574-H2582
Abstract: Cardiomyocytes from failing hearts exhibit reduced levels of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA) and/or increased activity of the endogenous SERCA inhibitor phospholamban. The resulting reduction in the Ca(2+) affinity of SERCA impairs SR Ca(2+) cycling in this condition. We have previously investigated the physiological impact of increasing the Ca(2+) affinity of SERCA by substituting SERCA2a with the higher affinity SERCA2b pump. When phospholamban was also ablated, these double knockouts (DKO) exhibited a dramatic reduction in total SERCA levels, severe hypertrophy, and diastolic dysfunction. We presently examined the role of cardiomyocyte Ca(2+) homeostasis in both functional and structural remodeling in these hearts. Despite the low SERCA levels in DKO, we observed near-normal Ca(2+) homeostasis with rapid Ca(2+) reuptake even at high Ca(2+) loads and stimulation frequencies. Well-preserved global Ca(2+) homeostasis in DKO was paradoxically associated with marked activation of the Ca(2+)-dependent nuclear factor of activated T-cell-calcineurin pathway known to trigger hypertrophy. No activation of the MAP kinase signaling pathway was detected. These findings suggest that local changes in Ca(2+) homeostasis may play an important signaling role in DKO, perhaps due to reduced microdomain Ca(2+) buffering by SERCA2b. Furthermore, alterations in global Ca(2+) homeostasis can also not explain impaired in vivo diastolic function in DKO. Taken together, our results suggest that normalizing global cardiomyocyte Ca(2+) homeostasis does not necessarily protect against hypertrophy and heart failure development and that excessively increasing SERCA Ca(2+) affinity may be detrimental.
URI: 
ISSN: 0363-6135
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Experimental Cardiology
Laboratory of Cellular Transport Systems
× corresponding author
# (joint) last author

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