Enhanced myofilament responsiveness upon β-adrenergic stimulation in post-infarct remodeled myocardium
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 3weeks after MI or sham. Single permeabilized cardiomyocytes demonstrated reduced maximal force (Fmax) and higher Ca2+-sensitivity in MI compared to sham. Fmaxdid not change during dobutamine infusion in sham, but markedly increased in MI. Moreover, the dobutamine-induced decrease in Ca2+-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 Ca2+-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.
|Keywords||-dependent calmodulin kinase II, 2+, Adrenergic stimulation, Ca, Contractility, Myocardial infarction, Phosphorylation|
|Persistent URL||dx.doi.org/10.1016/j.yjmcc.2010.12.002, hdl.handle.net/1765/31529|
Boontje, N.M., Merkus, D., Zaremba, R., Versteilen, A., de Waard, M.C., Mearini, G., … van der Velden, J.. (2011). Enhanced myofilament responsiveness upon β-adrenergic stimulation in post-infarct remodeled myocardium. Journal of Molecular and Cellular Cardiology, 50(3), 487–499. doi:10.1016/j.yjmcc.2010.12.002