Cardiovascular Research

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 Velden^a,*, Z Papp^b, R Zaremba^a, N.M Boontje^a, J.W de Jong^c, V.J Owen^d, P.B.J Burton^d, P Goldmann^e, K Jaquet^e and G.J.M Stienen^a

^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 (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 (pCa₅₀=0.20) than in donor (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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