Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Andrii Boguslavskyi, Davor Pavlovic, Karen Aughton, James E Clark, Jacqueline Howie, William Fuller, Michael J Shattock

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Aims: Elevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force-frequency relationship and arrhythmias. While phospholemman (PLM) is recognized to form the link between signaling 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 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 hypo-phosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3d post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na]i. Echocardiography, morphometry and PV catheterisation confirmed remodeling, dilation and contractile dysfunction. 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 was significantly exacerbated in banded PLM3SA mice compared to banded WT.

Conclusions: Decreased phosphorylation PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction and adverse remodeling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure.
Original languageEnglish
Pages (from-to)72-78
Number of pages6
JournalCardiovascular Research
Volume104
Early online date7 Aug 2014
DOIs
Publication statusPublished - 1 Oct 2014

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