Copyright © 2005, European Society of Cardiology
Role of phosphorylation of Thr17 residue of phospholamban in mechanical recovery during hypercapnic acidosis
aCentro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, 60 y 120, (1900) La Plata, Argentina
bDepartment of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 4567-0575, USA
* Corresponding author. Tel./fax: +54 221 483 4833. Email address: ramattia{at}atlas.med.unlp.edu.ar
Objectives: To assess the time course of phosphorylation of phospholamban residues, the underlying mechanisms determining these phosphorylations, and their functional impact on the mechanical recovery during acidosis.
Methods: Langendorff perfused rat hearts were submitted to 30 min of hypercapnic acidosis. Contractility, relaxation, and phosphorylation of phospholamban residues, immunodetected by specific antibodies, were determined.
Results: Acidosis produced a mechanical impairment followed by a spontaneous recovery, most of which occurred within the first 3 min of acidosis (early recovery). During this period, contractility and relaxation recovered by 67 ± 9% and 77 ± 11%, respectively, from its maximal depression, together with an increase in the Ca2+-calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of Thr17. The CaMKII inhibitor KN-93, at 1, 5 and 10 µM, decreased Thr17 phosphorylation to basal levels and produced a similar impairment of the early relaxation recovery (50%). However, only 5 and 10 µM KN-93 inhibited the early contractile recovery and completely blunted the late mechanical recovery. Inhibition of the reverse mode of the Na+/Ca2+ exchanger by KB-R7943 decreased Thr17 phosphorylation but accelerated the early contractile recovery.
Conclusions: CaMKII-dependent Thr17 phosphorylation significantly increased at the beginning of acidosis, is responsible for 50% of the early relaxation recovery, and is linked to the activation of the reverse Na+/Ca2+ mode. The early contractile recovery and the late mechanical recovery are dependent on CaMKII but independent of the phosphorylation of the Thr17 residue of phospholamban. The reverse Na+/Ca2+ mode has an additional negative effect that opposes the early mechanical recovery.
KEYWORDS Myocardial acidosis; Phospholamban phosphorylation; CaMKII; Na+/Ca2+ exchanger; Contractile function
Time for primary review 22 days
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