Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
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
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Antoons Gudrun
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- Abstract:
- 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
- phospholamban
- frequency response