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Cardiovascular Research Advance Access originally published online on January 17, 2008
Cardiovascular Research 2008 78(1):71-78; doi:10.1093/cvr/cvn013
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Altered Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase {alpha}2-isoform in heart failure{dagger}

Fredrik Swift1,2,*, Jon Arne Kro Birkeland1,2, Nils Tovsrud1,2, Ulla H. Enger1,2, Jan Magnus Aronsen1,2, William E. Louch1,2, Ivar Sjaastad1,2,3 and Ole M. Sejersted1,2

1 Institute for Experimental Medical Research, Ullevaal University Hospital, Kirkeveien 166, N-0407 Oslo, Norway
2 Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway
3 Department of Cardiology, Ullevaal University Hospital, Oslo, Norway

* Corresponding author. Tel: +47 23016800; fax: +47 23016799. E-mail address: fredrik.swift{at}medisin.uio.no

Aims: The Na+/K+-ATPase (NKA) {alpha}2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the Na+/Ca2+-exchanger (NCX) and Ca2+ regulation through intracellular Na+ concentration ([Na+]i). We hypothesized that downregulation of the NKA {alpha}2-isoform during congestive heart failure (CHF) disturbs the link between Na+ and Ca2+, and thus the control of cardiomyocyte contraction.

Methods and results: NKA isoform and t-tubule distributions were studied using immunocytochemistry, confocal and electron microscopy in a post-infarction rat model of CHF. Sham-operated rats served as controls. NKA and NCX currents (INKA and INCX) were measured and {alpha}2-isoform current (INKA,{alpha}2) was separated from total INKA using 0.3 µM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of {alpha}2-isoforms in the t-tubules. In CHF, the t-tubule network had a disorganized appearance in both isolated cardiomyocytes and fixed tissue. This was associated with altered expression patterns of NKA {alpha}1- and {alpha}2-isoforms. INKA,{alpha}2 density was reduced by 78% in CHF, in agreement with decreased protein expression (74%). When INKA,{alpha}2 was blocked in Sham cardiomyocytes, contractile parameters converged with those observed in CHF. In Sham, abrupt activation of INKA led to a decrease in INCX, presumably due to local depletion of [Na+]i in the vicinity of NCX. This decrease was smaller when the {alpha}2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the {alpha}2-isoform is necessary to modulate local [Na+]i close to NCX.

Conclusion: Downregulation of the {alpha}2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude Ca2+ from cardiomyocytes.

KEYWORDS Heart failure; Na/K-ATPase; Na/Ca-exchanger; e–c coupling; Contractile function

Time for primary review: 16 days

{dagger} This work was performed at Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway.


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