Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 17, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn013
Altered Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase 
2-isoform in heart failure
1 Institute for Experimental Medical Research, Ullevaal University Hospital, 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: Fredrik Swift Institute for Experimental Medical Research Ullevaal University Hospital Kirkeveien 166 N-0407 Oslo, Norway Phone: 23016800/ Fax: 23016799/ e-mail: fredrik.swift{at}medisin.uio.no
Aim: The Na+/K+-ATPase (NKA) (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 hypothesised that downregulation of the NKA (2-isoform during congestive heart failure (CHF) disturbs the link between Na+ and Ca2+, and thus the control of cardiomyocyte contraction.
Methods: KA 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 (2-isoform current (INKA,(2) was separated from total INKA using 0.3 µM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of (2-isoforms in the t-tubules.
Results: In CHF, the t-tubule network had a disorganised appearance in both isolated cardiomyocytes and fixed tissue. This was associated with altered expression patterns of NKA (1- and (2-isoforms. INKA,(2 density was reduced by 78% in CHF, in agreement with decreased protein expression (74%). When INKA,(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 (2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the (2-isoform is necessary to modulate local [Na+]i close to NCX.
Conclusion: Downregulation of the (2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude Ca2+ from cardiomyocytes.
Time for primary review: 16
Work was performed at Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. J. Chorro, I. Trapero, L. Such-Miquel, F. Pelechano, L. Mainar, J. Canoves, A. Tormos, A. Alberola, L. Hove-Madsen, J. Cinca, et al. Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1860 - H1869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Hund, P. J. Wright, W. Dun, J. S. Snyder, P. A. Boyden, and P. J. Mohler Regulation of the ankyrin-B-based targeting pathway following myocardial infarction Cardiovasc Res, March 1, 2009; 81(4): 742 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Song, X.-Q. Zhang, J. Wang, E. Cheskis, T. O. Chan, A. M. Feldman, A. L. Tucker, and J. Y. Cheung Regulation of cardiac myocyte contractility by phospholemman: Na+/Ca2+ exchange versus Na+-K+-ATPase Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1615 - H1625. [Abstract] [Full Text] [PDF]
|
|