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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Antoons, G; Vangheluwe, P; Volders, PG; Bito, V; Holemans, P; Ceci, M; Wuytack, F; Caroni, P; Mubagwa, K; Sipido, KR.
Increased phospholamban phosphorylation limits the force-frequency response in the MLP-/- mouse with heart failure.
J Mol Cell Cardiol. 2006; 40(3):350-360 Doi: 10.1016/j.yjmcc.2005.12.002
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Antoons Gudrun

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Reduced Ca(2+) release from the sarcoplasmic reticulum (SR) and a negative force-frequency relation characterize end-stage human heart failure. The MLP(-/-) mouse with dilated cardiomyopathy is used as a model to explore novel therapeutic interventions but the alterations in Ca(2+) handling in MLP(-/-) remain incompletely understood. We studied [Ca(2+)](i) in left ventricular myocytes from MLP(-/-) and WT mice (3-4 months old; whole-cell voltage clamp, 30 degrees C). At 1 Hz stimulation, the amplitude of [Ca(2+)](i) transients was similar. However, in contrast to WT, at higher frequencies the [Ca(2+)](i) transient amplitude declined in MLP(-/-) and there was no increase in SR Ca(2+) content. Unexpectedly, the decline of [Ca(2+)](i) was faster in MLP(-/-) than in WT (at 1 Hz, tau of 80 +/- 9 vs. 174 +/- 29 ms, P < 0.001) and the frequency-dependent acceleration of the decline was abolished suggesting an enhanced basal SERCA activity. Indeed, the Ca(2+) affinity of SR Ca(2+) uptake in homogenates was higher in MLP(-/-), with the maximal uptake rate similar to WT. Phosphorylation of phospholamban in MLP(-/-) was increased (2.3-fold at Ser(16) and 2.9-fold at the Thr(17) site, P < 0.001) with similar SERCA and total phospholamban protein levels. On increasing stimulation frequency to 4 Hz, WT, but not MLP(-/-), myocytes had a net gain of Ca(2+), suggesting inadequate Ca(2+) sequestration in MLP(-/-). In conclusion, increased baseline phosphorylation of phospholamban in MLP(-/-) leads to a reduced reserve for frequency-dependent increase of Ca(2+) release. This represents a novel paradigm for altered Ca(2+) handling in heart failure, underscoring the importance of phosphorylation pathways.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Calcium - analysis Calcium - metabolism
Calcium Channels, L-Type - metabolism
Calcium-Binding Proteins - metabolism
Electric Stimulation -
Heart Diseases - metabolism
Heart Ventricles - cytology
Mice -
Mice, Knockout -
Myocytes, Cardiac - metabolism
Phosphorylation -
Sarcoplasmic Reticulum - metabolism

Find related publications in this database (Keywords)
heart failure
sarcoplasmic reticulum
frequency response
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