title: Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman.
abstract: OBJECTIVE
  Elevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force-frequency relationship, and arrhythmias. Although phospholemman (PLM) is recognized to form the link between signalling pathways and Na/K pump activity, the possibility that defects in its regulation contribute to elevation of intracellular Na has not been investigated. Our aim was to test the hypothesis that the prevention of PLM phosphorylation in a PLM(3SA) knock-in mouse (in which PLM has been rendered unphosphorylatable) will exacerbate cardiac hypertrophy and cellular Na overload. Testing this hypothesis should determine whether changes in PLM phosphorylation are simply bystander effects or are causally involved in disease progression.
  
  
  RESULTS
  In wild-type (WT) mice, aortic constriction resulted in hypophosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3 days post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na]i. Echocardiography, morphometry, and pressure-volume (PV) catheterization confirmed remodelling, dilation, and contractile dysfunction, respectively. In PLM(3SA) mice, expression of Na/K ATPase was increased and PLM decreased such that net Na/K pump current under quiescent conditions was unchanged (cf. WT myocytes); [Na(+)]i was increased and forward-mode Na/Ca exchanger was reduced in paced PLM(3SA) myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM(3SA) mice compared with banded WT.
  
  
  CONCLUSIONS
  Decreased phosphorylation of PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction, and adverse remodelling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure.
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: Andrii
authors.initials: A
authors.lastname: Boguslavskyi
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: Davor
authors.initials: D
authors.lastname: Pavlovic
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Aughton
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Clark
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Dundee, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Howie
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, University of Dundee, Dundee, UK.
authors.forename: William
authors.initials: W
authors.lastname: Fuller
authors.affiliation: Cardiovascular Division, King's College London, London, UK michael.shattock@kcl.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shattock
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D005838:Genotype; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D008565:Membrane Proteins; D010750:Phosphoproteins; D019831:Sodium-Calcium Exchanger; C069141:phospholemman; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Hypertrophy; Intracellular sodium; Na/K ATPase; Phospholemman
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