%0 Journal Article %1 Swif_2008_71 %A Swift, Fredrik %A Birkeland, Jon Arne Kro %A Tovsrud, Nils %A Enger, Ulla H %A Aronsen, Jan Magnus %A Louch, William E %A Sjaastad, Ivar %A Sejersted, Ole M %D 2008 %J Cardiovasc. Res. %K imported %N 1 %P 71--78 %R 10.1093/cvr/cvn013 %T Altered Na$^+$/Ca$^2+$-exchanger activity due to downregulation of Na$^+$/K$^+$-ATPase alpha2-isoform in heart failure. %U http://dx.doi.org/10.1093/cvr/cvn013 %V 78 %X AIMS: The Na$^+$/K$^+$-ATPase (NKA) alpha2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the Na$^+$/Ca(+-exchanger (NCX) and Ca$^2+$ regulation through intracellular Na$^+$ concentration (Na$^+$i). We hypothesized that downregulation of the NKA alpha2-isoform during congestive heart failure (CHF) disturbs the link between Na$^+$ and Ca$^2+$, 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 (I NKA and I NCX) were measured and alpha2-isoform current (I NKA,alpha2) was separated from total I NKA using 0.3 microM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of alpha2-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 alpha1- and alpha2-isoforms. I NKA,alpha2 density was reduced by 78\% in CHF, in agreement with decreased protein expression (74\%). When I NKA,alpha2 was blocked in Sham cardiomyocytes, contractile parameters converged with those observed in CHF. In Sham, abrupt activation of I NKA led to a decrease in I NCX, presumably due to local depletion of Na$^+$i in the vicinity of NCX. This decrease was smaller when the alpha2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the alpha2-isoform is necessary to modulate local Na$^+$i close to NCX. CONCLUSION: Downregulation of the alpha2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude Ca$^2+$ from cardiomyocytes.

@article{Swif_2008_71, abstract = {AIMS: The {N}a$^{+}$/{K}$^{+}$-ATPase (NKA) alpha2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the {N}a$^{+}$/Ca(+-exchanger (NCX) and {C}a$^{2+}$ regulation through intracellular {N}a$^{+}$ concentration ([{N}a$^{+}$]i). We hypothesized that downregulation of the NKA alpha2-isoform during congestive heart failure (CHF) disturbs the link between {N}a$^{+}$ and {C}a$^{2+}$, 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 (I NKA and I NCX) were measured and alpha2-isoform current (I NKA,alpha2) was separated from total I NKA using 0.3 microM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of alpha2-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 alpha1- and alpha2-isoforms. I NKA,alpha2 density was reduced by 78\% in CHF, in agreement with decreased protein expression (74\%). When I NKA,alpha2 was blocked in Sham cardiomyocytes, contractile parameters converged with those observed in CHF. In Sham, abrupt activation of I NKA led to a decrease in I NCX, presumably due to local depletion of [{N}a$^{+}$]i in the vicinity of NCX. This decrease was smaller when the alpha2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the alpha2-isoform is necessary to modulate local [{N}a$^{+}$]i close to NCX. CONCLUSION: Downregulation of the alpha2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude {C}a$^{2+}$ from cardiomyocytes.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Swift, Fredrik and Birkeland, Jon Arne Kro and Tovsrud, Nils and Enger, Ulla H and Aronsen, Jan Magnus and Louch, William E and Sjaastad, Ivar and Sejersted, Ole M}, biburl = {https://www.bibsonomy.org/bibtex/2658fa83579aecff7aa51b00e899602bc/hake}, description = {The whole bibliography file I use.}, doi = {10.1093/cvr/cvn013}, file = {Swif_2008_71.pdf:Swif_2008_71.pdf:PDF}, institution = {Institute for Experimental Medical Research, Ullevaal University Hospital, Kirkeveien 166, N-0407 Oslo, Norway. fredrik.swift@medisin.uio.no}, interhash = {bb084777f28a10d59255f8f6284efd74}, intrahash = {658fa83579aecff7aa51b00e899602bc}, journal = {Cardiovasc. Res.}, keywords = {imported}, month = Apr, number = 1, pages = {71--78}, pdf = {Swif_2008_71.pdf}, pii = {cvn013}, pmid = {18203708}, timestamp = {2009-06-03T11:21:33.000+0200}, title = {Altered {N}a$^{+}$/{C}a$^{2+}$-exchanger activity due to downregulation of {N}a$^{+}$/{K}$^{+}$-ATPase alpha2-isoform in heart failure.}, url = {http://dx.doi.org/10.1093/cvr/cvn013}, volume = 78, year = 2008 }