title: Enhanced myofilament responsiveness upon β-adrenergic stimulation in post-infarct remodeled myocardium.
abstract: Previously we showed that left ventricular (LV) responsiveness to exercise-induced increases in noradrenaline was blunted in pigs with a recent myocardial infarction (MI) [van der Velden et al. Circ Res. 2004], consistent with perturbed β-adrenergic receptor (β-AR) signaling. Here we tested the hypothesis that abnormalities at the myofilament level underlie impaired LV responsiveness to catecholamines in MI. Myofilament function and protein composition were studied in remote LV biopsies taken at baseline and during dobutamine stimulation 3 weeks after MI or sham. Single permeabilized cardiomyocytes demonstrated reduced maximal force (F(max)) and higher Ca(2+)-sensitivity in MI compared to sham. F(max) did not change during dobutamine infusion in sham, but markedly increased in MI. Moreover, the dobutamine-induced decrease in Ca(2+)-sensitivity was significantly larger in MI than sham. Baseline phosphorylation assessed by phosphostaining of β-AR target proteins myosin binding protein C (cMyBP-C) and troponin I (cTnI) in MI and sham was the same. However, the dobutamine-induced increase in overall cTnI phosphorylation and cTnI phosphorylation at protein kinase A (PKA)-sites (Ser23/24) was less in MI compared to sham. In contrast, the dobutamine-induced phosphorylation of cMyBP-C at Ser282 was preserved in MI, and coincided with increased autophosphorylation (at Thr282) of the cytosolic Ca(2+)-dependent calmodulin kinase II (CaMKII-δC). In conclusion, in post-infarct remodeled myocardium myofilament responsiveness to dobutamine is significantly enhanced despite the lower increase in PKA-mediated phosphorylation of cTnI. The increased myofilament responsiveness in MI may depend on the preserved cMyBP-C phosphorylation possibly resulting from increased CaMKII-δC activity and may help to maintain proper diastolic performance during exercise.
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: Ruud
authors.initials: R
authors.lastname: Zaremba
authors.forename: Amanda
authors.initials: A
authors.lastname: Versteilen
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Giulia
authors.initials: G
authors.lastname: Mearini
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: de Beer
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013552:Swine; D019210:Troponin I / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D000099163:Myosin Binding Protein C
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D002395:Catecholamines; D017868:Cyclic AMP-Dependent Protein Kinases; D004280:Dobutamine; D011943:Receptors, Adrenergic, beta; D019210:Troponin I; D000099163:Myosin Binding Protein C