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Cardiovascular Research 2003 57(1):37-47; doi:10.1016/S0008-6363(02)00606-5
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins

J van der Veldena,*, Z Pappb, R Zarembaa, N.M Boontjea, J.W de Jongc, V.J Owend, P.B.J Burtond, P Goldmanne, K Jaquete and G.J.M Stienena

aLaboratory for Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
bUDMHSC Department of Cardiology, Debrecen, Hungary
cThorax Center, Erasmus University, Rotterdam, The Netherlands
dDepartment of Cardiac Surgery, National Heart and Lung Institute at the Imperial College School of Medicine, London, UK
eRuhr-Universität, Institut für Physiologische Chemie, Abteilung für Biochemie Supramolekularer Systeme, Bochum, Germany

* Corresponding author. Tel.: +31-20-444-8121; fax: +31-20-444-8255 j.van_der_velden.physiol{at}med.vu.nl

Objective: The alterations in contractile proteins underlying enhanced Ca2+-sensitivity of the contractile apparatus in end-stage failing human myocardium are still not resolved. In the present study an attempt was made to reveal to what extent protein alterations contribute to the increased Ca2+-responsiveness in human heart failure. Methods: Isometric force and its Ca2+-sensitivity were studied in single left ventricular myocytes from non-failing donor (n=6) and end-stage failing (n=10) hearts. To elucidate which protein alterations contribute to the increased Ca2+-responsiveness isoform composition and phosphorylation status of contractile proteins were analysed by one- and two-dimensional gel electrophoresis and Western immunoblotting. Results: Maximal tension did not differ between myocytes obtained from donor and failing hearts, while Ca2+-sensitivity of the contractile apparatus (pCa50) was significantly higher in failing myocardium ({Delta}pCa50=0.17). Protein analysis indicated that neither re-expression of atrial light chain 1 and fetal troponin T (TnT) nor degradation of myosin light chains and troponin I (TnI) are responsible for the observed increase in Ca2+-responsiveness. An inverse correlation was found between pCa50 and percentage of phosphorylated myosin light chain 2 (MLC-2), while phosphorylation of MLC-1 and TnT did not differ between donor and failing hearts. Incubation of myocytes with protein kinase A decreased Ca2+-sensitivity to a larger extent in failing ({Delta}pCa50=0.20) than in donor ({Delta}pCa50=0.03) myocytes, abolishing the difference in Ca2+-responsiveness. An increased percentage of dephosphorylated TnI was found in failing hearts, which significantly correlated with the enhanced Ca2+-responsiveness. Conclusions: The increased Ca2+-responsiveness of the contractile apparatus in end-stage failing human hearts cannot be explained by a shift in contractile protein isoforms, but results from the complex interplay between changes in the phosphorylation status of MLC-2 and TnI.

KEYWORDS Contractile function; Heart failure; Myocytes; Protein phosphorylation


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