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001-es BibID:	BIBFORM010421
Első szerző:	Hamdani, Nazha
Cím:	Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction / Hamdani, N., Paulus, W. J., van Heerebeek, L., Borbely, A., Boontje, N. M., Zuidwijk, M. J., Bronzwaer, J. G., Simonides, W. S., Niessen, H. W., Stienen, G. J. M., van der Velden, J.
Dátum:	2009
ISSN:	0195-668X (Print)
Megjegyzések:	Left ventricular (LV) myocardial structure and function differ in heart failure (HF) with normal (N) and reduced (R) LV ejection fraction (EF). This difference could underlie an unequal outcome of trials with beta-blockers in heart failure with normal LVEF (HFNEF) and heart failure with reduced LVEF (HFREF) with mixed results observed in HFNEF and positive results in HFREF. To investigate whether beta-blockers have distinct myocardial effects in HFNEF and HFREF, myocardial structure, cardiomyocyte function, and myocardial protein composition were compared in HFNEF and HFREF patients without or with beta-blockers. METHODS AND RESULTS: Patients, free of coronary artery disease, were divided into beta-(HFNEF) (n = 16), beta+(HFNEF) (n = 16), beta-(HFREF) (n = 17), and beta+(HFREF) (n = 22) groups. Using LV endomyocardial biopsies, we assessed collagen volume fraction (CVF) and cardiomyocyte diameter (MyD) by histomorphometry, phosphorylation of myofilamentary proteins by ProQ-Diamond phosphostained 1D-gels, and expression of beta-adrenergic signalling and calcium handling proteins by western immunoblotting. Cardiomyocytes were also isolated from the biopsies to measure active force (F(active)), resting force (F(passive)), and calcium sensitivity (pCa(50)). Myocardial effects of beta-blocker therapy were either shared by HFNEF and HFREF, unique to HFNEF or unique to HFREF. Higher F(active), higher pCa(50), lower phosphorylation of troponin I and myosin-binding protein C, and lower beta(2) adrenergic receptor expression were shared. Higher F(passive), lower CVF, lower MyD, and lower expression of stimulatory G protein were unique to HFNEF and lower expression of inhibitory G protein was unique to HFREF. CONCLUSION: Myocardial effects unique to either HFNEF or HFREF could contribute to the dissimilar outcome of beta-blocker therapy in both HF phenotypes.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Adrenergic beta-Antagonists Aged Cross-Sectional Studies Female Heart Failure Humans Male Microfilament Proteins Middle Aged Myocardium Myocytes, Cardiac Phosphorylation Stroke Volume Ventricular Dysfunction, Left
Megjelenés:	European Heart Journal. - 30 : 15 (2009), p. 1863-1872. -
További szerzők:	Paulus, Walter J. Heerebeek, Loek, van Borbély Attila (1978-) (kardiológus) Boontje, Nicky M. Zuidwijk, Marian J. Bronzwaer, Jean G. F. Simonides, Warner S. Niessen, Hans W. M. Stienen, Ger J. M. Velden, Jolanda, van der
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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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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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