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Hypertrophy, increased ejection fraction, and reduced Na-K-ATPase activity in phospholemman-deficient mice

¹Division of Cardiovascular Medicine, ²Cardiovascular Research Center, ³Department of Molecular Physiology and Biological Physics, ⁴Department of Radiology, ⁵Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia; ⁶Laboratory of Membrane Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; ⁷Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana; ⁸Transgenic Biology, Penn State University, University Park, Pennsylvania

Submitted 12 February 2004 ; accepted in final form 22 November 2004

Phospholemman (FXYD1), a 72-amino acid transmembrane protein abundantly expressed in the heart and skeletal muscle, is a major substrate for phosphorylation in the cardiomyocyte sarcolemma. Biochemical, cellular, and electrophysiological studies have suggested a number of possible roles for this protein, including ion channel modulator, taurine-release channel, Na⁺/Ca²⁺ exchanger modulator, and Na-K-ATPase-associated subunit. We have generated a phospholemman-deficient mouse. The adult null mice exhibited increased cardiac mass, larger cardiomyocytes, and ejection fractions that were 9% higher by magnetic resonance imaging compared with wild-type animals. Notably, this occurred in the absence of hypertension. Total Na-K-ATPase activity was 50% lower in the phospholemman-deficient hearts. Expression (per unit of membrane protein) of total Na-K-ATPase was only slightly diminished, but expression of the minor ₂-isoform, which has been specifically implicated in the control of contractility, was reduced by 60%. The absence of phospholemman thus results in a complex response, including a surprisingly large reduction in intrinsic Na-K-ATPase activity, changes in Na-K-ATPase isoform expression, increase in ejection fraction, and increase in cardiac mass. We hypothesize that a primary effect of phospholemman is to modulate the Na-K-ATPase and that its reduced activity initiates compensatory responses.

FXYD protein family; heart; mouse; knockout

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