Expression and Phosphorylation of the Na-Pump Regulatory Subunit Phospholemman in Heart Failure

Author:

Bossuyt Julie1,Ai Xun1,Moorman J. Randall1,Pogwizd Steven M.1,Bers Donald M.1

Affiliation:

1. From the Department of Physiology (J.B., D.M.B.), Loyola University Chicago, Maywood, Ill; Department of Medicine (X.A., S.M.P.), University of Illinois, Chicago; Division of Cardiology (J.R.M.), Department of Internal Medicine, University of Virginia, Charlottesville.

Abstract

Intracellular [Na] is ≈3 mmol/L higher in heart failure (HF; in our arrhythmogenic rabbit model; 3 ), and this can profoundly affect cardiac Ca and contractile function via Na/Ca exchange and Na/H exchange. Na/K-ATPase is the primary mechanism of Na extrusion. We examine here in HF rabbits (and human hearts) expression of Na/K-ATPase isoforms and phospholemman (PLM), a putative Na/K-ATPase regulatory subunit that inhibits pump function and is a major cardiac phosphorylation target. Na/K-ATPase α1- and α2-isoforms were reduced in HF in rabbit ventricular homogenates (by 24%) and isolated myocytes (by 30% and 17%), whereas α3 was increased (50%) in homogenates and decreased (52%) in myocytes ( P <0.05). Homogenate Na/K-ATPase activity in left ventricle was also decreased in HF. However, we showed previously that Na/K-ATPase characteristics in intact ventricular myocytes were unaltered in HF. To reconcile these findings, we assessed PLM expression, phosphorylation, and association with Na/K-ATPase. PLM coimmunoprecipitated with Na/K-ATPase α1 and α2 in control and HF rabbit myocytes. PLM expression was reduced in HF by 42% in isolated rabbit left ventricular (LV) myocytes, by 48% in rabbit LV homogenates, and by 24% in human LV homogenate. The fraction of PLM phosphorylated at Ser-68 was increased dramatically in HF. Our results are consistent with a role for PLM analogous to that of phospholamban for SR Ca-ATPase (SERCA): inhibition of Na/K-ATPase function that is relieved on PLM phosphorylation. So reduced Na/K-ATPase expression in HF may be functionally offset by lower inhibition by PLM (because of reduced PLM expression and higher PLM phosphorylation).

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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