Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy

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Abstract
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 μg·kg−1·min−1dobutamine, 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-Thr17phosphorylation 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-Thr17and diminished inotropic responsiveness and PLB-Ser16phosphorylation 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-Thr17phosphorylation, suggesting that activation of CaMKII in PO hypertrophy contributes to defective adrenergic reserve in compensated LVH and early heart failure.