title: Hypertrophy, increased ejection fraction, and reduced Na-K-ATPase activity in phospholemman-deficient mice.
abstract: 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(+)/Ca(2+) 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 alpha(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.
authors.affiliation: Dividsion of Cardiovascular Medicine, Box 801394 MR5, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Li-Guo
authors.initials: LG
authors.lastname: Jia
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnet
authors.forename: Roberta C
authors.initials: RC
authors.lastname: Bogaev
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Blatt
authors.forename: Cindy E
authors.initials: CE
authors.lastname: McKinney
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Day
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.forename: Larry R
authors.initials: LR
authors.lastname: Jones
authors.forename: J Randall
authors.initials: JR
authors.lastname: Moorman
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Sweadner
authors.forename: Amy L
authors.initials: AL
authors.lastname: Tucker
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D004789:Enzyme Activation; D007763:Lac Operon; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D012508:Sarcolemma / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D013318:Stroke Volume / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D010750:Phosphoproteins; C069141:phospholemman; D000254:Sodium-Potassium-Exchanging ATPase