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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 291; no. 1; p. 30
• Main Authors: Mills, Geoffrey D, Kubo, Hajime, Harris, David M, Berretta, Remus M
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 01.07.2006
• Subjects: Cardiology; Heart; Hypotheses; Phosphates; Proteins; Stress
• ISSN: 0363-6135; 1522-1539

Physiological hemodynamic stress, such as aerobic exercise, is intermittent and requires an increase in Ca^sup 2+^-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 (P0)-induced cardiac hypertrophy is caused by abnormalities in the abundance and/or basal phosphorylation state of Ca^sup 2+^ regulatory proteins. P0, 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^sup -1^*min^sup -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-Thr^sup 17^, P < 0.05) but not at the protein kinase A-specific site (PLB-Ser^sup 16^). PLB-Thr^sup 17^ phosphorylation was inversely correlated with dobutamine-induced increases in contractility in PO animals (r^sup 2^ = 0.81, P < 0.05). Continuous induction of Ca^sup 2+^ transients in isolated ventricular myocytes for 24 h increased phosphorylation at PLB-Thr^sup 17^ and diminished inotropic responsiveness and PLB-Ser^sup 16^ 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-Thr^sup 17^ phosphorylation, suggesting that activation of CaMKII in PO hypertrophy contributes to defective adrenergic reserve in compensated LVH and early heart failure. [PUBLICATION ABSTRACT]