Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy.
Physiological hemodynamic stress, such as aerobic exercise, is intermittent and requires an increase in Ca2+ -dependent contractility through sympathetic nervous system activation. Pathological hemodynamic stress, such as hypertension, is persistent and requires sustained increases in cardiac function. Over time, this causes left ventricular hypertrophy (LVH)-reduced responsiveness to sympathetic stimulation. In this study, we examined the hypothesis that blunted in vivo adrenergic contractile responsiveness in pressure overload (PO)-induced cardiac hypertrophy is caused by abnormalities in the abundance and/or basal phosphorylation state of Ca2+ regulatory proteins. PO, induced by aortic constriction, caused concentric LVH or dilated LVH. Only animals with dilation exhibited a decrease in baseline left ventricle function [fractional area change (FAC); measured with echocardiography]. All PO animals had a reduced contractile response to adrenergic agonists (increase in FAC with 40 microg.kg(-1).min(-1) dobutamine, control 0.30 +/- 0.04, n = 5 vs. banded 0.10 +/- 0.03, n = 10; P < 0.01). PO animals had reduced phospholamban (PLB) protein abundance (P = 0.07, not significant) and increased PLB phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLB-Thr17, P < 0.05) but not at the protein kinase A-specific site (PLB-Ser16). PLB-Thr17 phosphorylation was inversely correlated with dobutamine-induced increases in contractility in PO animals (r2 = 0.81, P < 0.05). Continuous induction of Ca2+ transients in isolated ventricular myocytes for 24 h increased phosphorylation at PLB-Thr17 and diminished inotropic responsiveness and PLB-Ser16 phosphorylation after exposure to isoproterenol (P < 0.05). These data show that reduced adrenergic responsiveness in feline PO hypertrophy and failure involves increases in basal PLB-Thr17 phosphorylation, suggesting that activation of CaMKII in PO hypertrophy contributes to defective adrenergic reserve in compensated LVH and early heart failure.
Mills
Geoffrey D
GD
Temple University School of Medicine, Philadelphia, PA 19140, USA.
Kubo
Hajime
H
Harris
David M
DM
Berretta
Remus M
RM
Piacentino
Valentino
V
Houser
Steven R
SR
D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D002415:Cats; D002908:Chronic Disease; D019317:Evidence-Based Medicine; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology*; D009200:Myocardial Contraction; D010766:Phosphorylation; D011312:Pressure; D011485:Protein Binding; D011941:Receptors, Adrenergic / Q000378:metabolism; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology*; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D011941:Receptors, Adrenergic; D013912:Threonine; D000099211:Phospholamban