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Reduced sarcoplasmic reticulum Ca2+-ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium

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Abstract

Human hibernating myocardium (HHM) is characterized by reversible contractile dysfunction during chronic ischemia. A disturbed calcium-homeostasis is a decisive factor for reduced functional capacity in heart diseases. We therefore investigated calcium-handling proteins in HHM. In 12 patients suffering from multi-vessel coronary artery disease and contractile dysfunction with indication for bypass surgery, HHM was detected preoperatively by thallium scintigraphy, radionuclide ventriculography and dobutamine echocardiography. Transmural biopsies of these regions were taken and analyzed by immunohistochemistry and electron microscopy. Furthermore, SR-calcium ATPase (SERCA2a), phospholamban (PLN), the phosphorylated forms of PLN (PLN-Ser16, PLN-Thr17) as well as sodium-calcium exchanger (NCX) and ryanodine receptor (RyR2) were investigated by RT-PCR and Western-blotting. Additionally, SERCA2a activity was measured by an enzyme-coupled assay. In all patients complete functional recovery could be documented 3 months after revascularization by repeating all preoperative investigations. In HHM maximal SERCA2a activity was significantly reduced (HHM: 424.5± 33.9, control: 609.0± 48.5 nmol ATP mg protein−1 min−1, p≤ 0.05), whereas SERCA2a protein levels were unchanged. mRNA levels (HHM: 1.36± 0.08 vs. control: 0.78± 0.04, p≤ 0.05) and protein amount (HHM:1.67± 0.14 vs. control: 1.00± 0.04, p≤ 0.05) of PLN (A1) were increased resulting in an increased PLN:SERCA2a-ratio. PLN-Ser16 (HHM: 0.60± 0.08 vs. control: 1.00± 0.11, p≤ 0.05) and PLN-Thr17 (HHM: 0.63± 0.11 vs. control: 1.00± 0.06, p≤ 0.05) phosphorylation was significantly decreased. RyR2 and NCX showed no significant alteration. In HHM a decreased activity of SERCA2a due to an impaired phosphorylation of PLN contributes to contractile dysfunction. The increase in the relative ratio of PLN/SERCA2a leads to a decreased calcium affinity of SERCA2a.

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Authors and Affiliations

  1. Department of Cardiology, Kerckhoff Heart Centre, Benekestr. 2–8, Bad Nauheim, 61231, Germany

    Holger M. Nef, Helge Möllmann, Ch. Hamm (MD) & Albrecht Elsässer

  2. Department of Heart Surgery, Kerckhoff Heart Centre, Bad Nauheim, Germany

    Woitek Skwara

  3. Laboratory of Muscle Research and Molecular Cardiology, Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany

    Birgit Bölck & Robert H. G. Schwinger

  4. Department of Experimental Cardiology, Max-Planck-Institute for Physiological and Clinical Research (W.G. Kerckhoff-Institute), Bad Nauheim, Germany

    Sawa Kostin & Jutta Schaper

Authors
  1. Holger M. Nef
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  2. Helge Möllmann
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  4. Birgit Bölck
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  5. Robert H. G. Schwinger
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  6. Ch. Hamm
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  7. Sawa Kostin
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  9. Albrecht Elsässer
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Correspondence to Albrecht Elsässer.

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Nef, H.M., Möllmann, H., Skwara, W. et al. Reduced sarcoplasmic reticulum Ca2+-ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. Mol Cell Biochem 282, 53–63 (2006). https://doi.org/10.1007/s11010-006-1171-7

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  • DOI: https://doi.org/10.1007/s11010-006-1171-7

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