Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Boguslavskyi, A., Pavlovic, D., Aughton, K., Clark, J. E., Howie, J., Fuller, W. and Shattock, M. J. (2014) Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman. Cardiovascular Research, 104(1), pp. 72-82. (doi: 10.1093/cvr/cvu182) (PMID:25103111) (PMCID:PMC4174889)

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Aims: 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 PLM3SA 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. Methods and 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 PLM3SA 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 PLM3SA myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM3SA 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.

Item Type:Articles
Additional Information:Thiswork wassupport bygrantfromtheBritishHeart Foundation(RG/12/4/ 29426 to M.J.S. and W.F.). Funding to pay the Open Access publication charges for this article was provided by the British Heart Foundation via the Charities Open Access Fund (COAF).
Glasgow Author(s) Enlighten ID:Fuller, Dr Will
Authors: Boguslavskyi, A., Pavlovic, D., Aughton, K., Clark, J. E., Howie, J., Fuller, W., and Shattock, M. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN (Online):1755-3245
Published Online:07 August 2014
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Cardiovascular Research 104(1):72-82
Publisher Policy:Reproduced under a Creative Commons License

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