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1.

001-es BibID:BIBFORM005631
Első szerző:Hamdani, Nazha
Cím:Myofilament dysfunction in cardiac disease from mice to men / Hamdani, N., de Waard, M., Messer, A. E., Boontje, N. M., Kooij, V., van Dijk, S., Versteilen, A., Lamberts, R., Merkus, D., Dos Remedios, C., Duncker, D. J., Borbely, A., Papp, Z., Paulus, W., Stienen, G. J. M., Marston, S. B., van der Velden, J.
Dátum:2008
ISSN:0142-4319 (Print)
Megjegyzések:In healthy human myocardium a tight balance exists between receptor-mediated kinases and phosphatases coordinating phosphorylation of regulatory proteins involved in cardiomyocyte contractility. During heart failure, when neurohumoral stimulation increases to compensate for reduced cardiac pump function, this balance is perturbed. The imbalance between kinases and phosphatases upon chronic neurohumoral stimulation is detrimental and initiates cardiac remodelling, and phosphorylation changes of regulatory proteins, which impair cardiomyocyte function. The main signalling pathway involved in enhanced cardiomyocyte contractility during increased cardiac load is the beta-adrenergic signalling route, which becomes desensitized upon chronic stimulation. At the myofilament level, activation of protein kinase A (PKA), the down-stream kinase of the beta-adrenergic receptors (beta-AR), phosphorylates troponin I, myosin binding protein C and titin, which all exert differential effects on myofilament function. As a consequence of beta-AR down-regulation and desensitization, phosphorylation of the PKA-target proteins within the cardiomyocyte may be decreased and alter myofilament function. Here we discuss involvement of altered PKA-mediated myofilament protein phosphorylation in different animal and human studies, and discuss the roles of troponin I, myosin binding protein C and titin in regulating myofilament dysfunction in cardiac disease. Data from the different animal and human studies emphasize the importance of careful biopsy procurement, and the need to investigate localization of kinases and phosphatases within the cardiomyocyte, in particular their co-localization with cardiac myofilaments upon receptor stimulation.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Muscle Research and Cell Motility. - 29 : 6-8 (2008), p. 189-201. -
További szerzők:de Waard, Monique Messer, Andrew E. Boontje, Nicky M. Kooij, Viola Dijk, Sabine, van Versteilen, Amanda Lamberts, Regis Merkus, Daphne Dos Remedios, Cris Duncker, Dirk J. Borbély Attila (1978-) (kardiológus) Papp Zoltán (1965-) (kardiológus, élettanász) Paulus, Walter J. Stienen, Ger J. M. Marston, Steven B. Velden, Jolanda, van der
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2.

001-es BibID:BIBFORM040606
Első szerző:Velden, Jolanda, van der
Cím:Calcium sensitivity of force in human ventricular cardiomyocytes from donor and failing hearts / van der Velden J., Boontje N. M., Papp Z., Klein L. J., Visser F. C., de Jong J. W., Owen V. J., Burton P. B., Stienen G. J.
Dátum:2002
ISSN:0300-8428
Megjegyzések:In failing human myocardium changes occur, in particular, in isoform composition and phosphorylation level of the troponin T (TnT) and troponin I (TnI) subunits of the actin filament and the myosin light chains (MLC-1 and -2), but it is unclear to what extent they influence cardiac performance. This overview concentrates on the relation between contractile function, contractile protein composition and phosphorylation levels in small biopsies from control (donor) hearts, from biopsies obtained during open heart surgery (NYHA Class I-IV) and from end-stage failing (explanted, NYHA class IV) hearts. Furthermore, attention is paid to the effect of the catalytic subunit of protein kinase A on isometric force development in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at different resting sarcomere lengths. A reduction in sarcomere length from 2.2 to 1.8 microm caused reductions in maximum isometric force by approximately 35% both in donor and in failing cardiomyocytes. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean delta pCa50 = 0.22). Our findings indicate that 1) TnI phosphorylation contributes to the differences in calcium sensitivity between donor and end-stage failing hearts, 2) human ventricular myocardium is heterogeneous with respect of the phosphorylation of TnT, MLC-2 and the isoform distribution of MLC-1 and MLC-2, and 3) the Frank-Starling mechanism is preserved in end-stage failing myocardium.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Basic Research In Cardiology. - 97 : Suppl.1 (2002), p. 118-126. -
További szerzők:Boontje, Nicky M. Papp Zoltán (1965-) (kardiológus, élettanász) Klein, L. J. Visser, F. C. de Jong, J. W. Owen, V. J. Burton, P. B. Stienen, Ger J. M.
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3.

001-es BibID:BIBFORM040584
Első szerző:Velden, Jolanda, van der
Cím:The effect of myosin light chain 2 dephosphorylation on Ca2+ -sensitivity of force is enhanced in failing human hearts / van der Velden J., Papp Z., Boontje N. M., Zaremba R., de Jong J. W., Janssen P. M., Hasenfuss G., Stienen G. J.
Dátum:2003
ISSN:0008-6363
Megjegyzések:OBJECTIVE: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1+/-2.0%) compared to donor (31.9+/-4.8%) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. METHODS: Cooperative effects in isometric force and rate of force redevelopment (K(tr)) were studied in single Triton-skinned human cardiomyocytes at various [Ca(2+)] before and after protein phosphatase-1 (PP-1) incubation. RESULTS: Maximum force and K(tr) values did not differ between failing and donor hearts, but Ca(2+)-sensitivity of force (pCa(50)) was significantly higher in failing myocardium (Deltap Ca(50)=0.17). K(tr) decreased with decreasing [Ca(2+)], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa(50) to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute K(tr) values was found after PP-1 in failing and donor myocytes, while the shape of the K(tr)-Ca(2+) relationships remained unaltered. CONCLUSIONS: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca(2+)-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca(2+)-sensitivity and impaired Ca(2+)-handling on diastolic function in human heart failure.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cardiovascular Research. - 57 : 2 (2003), p. 505-514. -
További szerzők:Papp Zoltán (1965-) (kardiológus, élettanász) Boontje, Nicky M. Zaremba, Ruud de Jong, J. W. Janssen, P. M. L. Hasenfuß, Gerd Stienen, Ger J. M.
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM040583
Első szerző:Velden, Jolanda, van der
Cím:Myosin light chain composition in non-failing donor and end-stage failing human ventricular myocardium / van der Velden J., Papp Z., Boontje N. M., Zaremba R., de Jong J. W., Janssen P. M. L., Hasenfuss G., Stienen G. J. M.
Dátum:2003
ISSN:0065-2598
Megjegyzések:The increased Ca(2+)-responsiveness in end-stage human heart failure cannot be attributed to contractile protein isoform changes, but rather is the complex resultant of changes in degree of phosphorylation of VLC-2 and TnI. Despite the decreased basal level of VLC-2 phosphorylation the response to VLC-2 dephosphorylation is enhanced in failing myocytes, which might result from differences in endogenous phosphorylation of thin and thick filament proteins between donor and failing hearts. Taken together decreased VLC-2 phosphorylation in end-stage human heart failure might represent a compensatory process leading to an improvement of myocardial contractility by opposing the detrimental effects of increased Ca(2+)-responsiveness of force and impaired Ca(2+)-handling on diastolic function.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Advances in Experimental Medicine and Biology. - 538 (2003), p. 3-15. -
További szerzők:Papp Zoltán (1965-) (kardiológus, élettanász) Boontje, Nicky M. Zaremba, Ruud de Jong, J. W. Janssen, P. M. L. Hasenfuß, Gerd Stienen, Ger J. M.
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5.

001-es BibID:BIBFORM040582
Első szerző:Velden, Jolanda, van der
Cím:Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins / van der Velden J., Papp Z., Zaremba R., Boontje N. M., de Jong J. W., Owen V. J., Burton P. B., Goldmann P., Jaquet K., Stienen G. J.
Dátum:2003
ISSN:0008-6363
Megjegyzések:OBJECTIVE: The alterations in contractile proteins underlying enhanced Ca(2+)-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 Ca(2+)-responsiveness in human heart failure. METHODS: Isometric force and its Ca(2+)-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 Ca(2+)-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 Ca(2+)-sensitivity of the contractile apparatus (pCa(50)) was significantly higher in failing myocardium (deltapCa(50)=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 Ca(2+)-responsiveness. An inverse correlation was found between pCa(50) 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 Ca(2+)-sensitivity to a larger extent in failing (deltapCa(50)=0.20) than in donor (deltapCa(50)=0.03) myocytes, abolishing the difference in Ca(2+)-responsiveness. An increased percentage of dephosphorylated TnI was found in failing hearts, which significantly correlated with the enhanced Ca(2+)-responsiveness.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cardiovascular Research. - 57 : 1 (2003), p. 37-47. -
További szerzők:Papp Zoltán (1965-) (kardiológus, élettanász) Zaremba, Ruud Boontje, Nicky M. de Jong, J. W. Owen, V. J. Burton, P. B. Goldmann, P. Jaquet, Kai Stienen, Ger J. M.
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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6.

001-es BibID:BIBFORM015092
Első szerző:Velden, Jolanda, van der
Cím:Functional effects of protein kinase C-mediated myofilament phosphorylation in human myocardium / van der Velden J., Narolska N. A., Lamberts R. R., Boontje N. M., Borbély A., Zaremba R., Bronzwaer J. G. F., Papp Z., Jaquet K., Paulus W. J., Stienen G. J.
Dátum:2006
ISSN:0008-6363
Megjegyzések:In human heart failure beta-adrenergic-mediated protein kinase A (PKA) activity is down-regulated, while protein kinase C (PKC) activity is up-regulated. PKC-mediated myofilament protein phosphorylation might be detrimental for contractile function in cardiomyopathy. This study was designed to reveal the effects of PKC on myofilament function in human myocardium under basal conditions and upon modulation of protein phosphorylation by PKA and phosphatases.METHODS: Isometric force was measured at different [Ca(2+)] in single permeabilized cardiomyocytes from non-failing and failing human left ventricular tissue. Basal phosphorylation of myofilament proteins and the influence of PKC, PKA, and phosphatase treatments were analyzed by one- and two-dimensional gel electrophoresis, Western immunoblotting, and ELISA.RESULTS: Troponin I (TnI) phosphorylation at the PKA sites was decreased in failing compared to non-failing hearts and correlated well with myofilament Ca(2+) sensitivity (pCa(50)). Incubation with the catalytic domain of PKC slightly decreased maximal force under basal conditions, but not following PKA and phosphatase pretreatments. PKC reduced Ca(2+) sensitivity to a larger extent in failing (DeltapCa(50)=0.19+/-0.03) than in non-failing (DeltapCa(50)=0.08+/-0.01) cardiomyocytes. This shift was reduced, though still significant, when PKC was preceded by PKA, while PKA following PKC did not further decrease pCa(50). Protein analysis indicated that PKC phosphorylated PKA sites in human TnI and increased phosphorylation of troponin T, while myosin light chain phosphorylation remained unaltered.CONCLUSION: In human myocardium PKC-mediated myofilament protein phosphorylation only has a minor effect on maximal force development. The PKC-mediated decrease in Ca(2+) sensitivity may serve to improve diastolic function in failing human myocardium in which PKA-mediated TnI phosphorylation is decreased.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cardiovascular Research. - 69 : 4 (2006), p. 876-887. -
További szerzők:Narolska, Nadiya A. Lamberts, Regis Boontje, Nicky M. Borbély Attila (1978-) (kardiológus) Zaremba, Ruud Bronzwaer, Jean G. F. Papp Zoltán (1965-) (kardiológus, élettanász) Jaquet, Kornelia Paulus, Walter J. Stienen, Ger J. M.
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