Myofilament dysfunction in cardiac disease from mice to men.
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.
Hamdani
Nazha
N
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
de Waard
Monique
M
Messer
Andrew E
AE
Boontje
Nicky M
NM
Kooij
Viola
V
van Dijk
Sabine
S
Versteilen
Amanda
A
Lamberts
Regis
R
Merkus
Daphne
D
Dos Remedios
Cris
C
Duncker
Dirk J
DJ
Borbely
Attila
A
Papp
Zoltan
Z
Paulus
Walter
W
Stienen
Ger J M
GJ
Marston
Steven B
SB
van der Velden
Jolanda
J
D008841:Actin Cytoskeleton / Q000473:pathology* / Q000502:physiology; D000818:Animals; D006331:Heart Diseases / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D013045:Species Specificity