title: Expression and phosphorylation of the na-pump regulatory subunit phospholemman in heart failure.
abstract: Intracellular [Na] is approximately 3 mmol/L higher in heart failure (HF; in our arrhythmogenic rabbit model), 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 alpha1- and alpha2-isoforms were reduced in HF in rabbit ventricular homogenates (by 24%) and isolated myocytes (by 30% and 17%), whereas alpha3 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 alpha1 and alpha2 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).
authors.affiliation: Department of Physiology, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Bossuyt
authors.forename: Xun
authors.initials: X
authors.lastname: Ai
authors.forename: J Randall
authors.initials: JR
authors.lastname: Moorman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pogwizd
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000818:Animals; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D021122:Protein Subunits; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; C069141:phospholemman; D000254:Sodium-Potassium-Exchanging ATPase