Selective phosphorylation of PKA targets after β-adrenergic receptor stimulation impairs myofilament function in Mybpc3-targeted HCM mouse model
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Selective phosphorylation of PKA targets after β-adrenergic receptor stimulation impairs myofilament function in Mybpc3-targeted HCM mouse model. / Najafi, Aref; Sequeira, Vasco; Helmes, Michiel; Bollen, Ilse AE; Goebel, Max; Regan, Jessica A; Carrier, Lucie; Kuster, Diederik W D; van der Velden, Jolanda.
in: CARDIOVASC RES, Jahrgang 110, Nr. 2, 2016, S. 200-14.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Selective phosphorylation of PKA targets after β-adrenergic receptor stimulation impairs myofilament function in Mybpc3-targeted HCM mouse model
AU - Najafi, Aref
AU - Sequeira, Vasco
AU - Helmes, Michiel
AU - Bollen, Ilse AE
AU - Goebel, Max
AU - Regan, Jessica A
AU - Carrier, Lucie
AU - Kuster, Diederik W D
AU - van der Velden, Jolanda
PY - 2016
Y1 - 2016
N2 - Aims : Hypertrophic cardiomyopathy (HCM) has been associated with reduced b-adrenergic receptor (b-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished b-AR signalling in HCM. We aimed to investigate the role of b-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G >A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C. Methods and results : Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca2+ sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force–sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values. Conclusion : These data provide evidence that in the KI HCM mouse model, b-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response.
AB - Aims : Hypertrophic cardiomyopathy (HCM) has been associated with reduced b-adrenergic receptor (b-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished b-AR signalling in HCM. We aimed to investigate the role of b-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G >A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C. Methods and results : Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca2+ sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force–sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values. Conclusion : These data provide evidence that in the KI HCM mouse model, b-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response.
M3 - SCORING: Journal article
VL - 110
SP - 200
EP - 214
JO - CARDIOVASC RES
JF - CARDIOVASC RES
SN - 0008-6363
IS - 2
ER -