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Overexpression of the Na+/K+ ATPase alpha2 but not alpha1 isoform attenuates pathological cardiac hypertrophy and remodeling.

Authors: Correll, RN  Eder, P  Burr, AR  Despa, S  Davis, J  Bers, DM  Molkentin, JD 
Citation: Correll RN, etal., Circ Res. 2014 Jan 17;114(2):249-56. doi: 10.1161/CIRCRESAHA.114.302293. Epub 2013 Nov 11.
Pubmed: (View Article at PubMed) PMID:24218169
DOI: Full-text: DOI:10.1161/CIRCRESAHA.114.302293

RATIONALE: The Na+ / K+ ATPase (NKA) directly regulates intracellular Na+ levels, which in turn indirectly regulates Ca2+ levels by proximally controlling flux through the Na+ / Ca2+ exchanger (NCX1). Elevated Na+ levels have been reported during heart failure, which permits some degree of reverse-mode Ca2+ entry through NCX1, as well as less efficient Ca2+ clearance. OBJECTIVE: To determine whether maintaining lower intracellular Na+ levels by NKA overexpression in the heart would enhance forward-mode Ca2+ clearance and prevent reverse-mode Ca2+ entry through NCX1 to protect the heart. METHODS AND RESULTS: Cardiac-specific transgenic mice overexpressing either NKA-alpha1 or NKA-alpha2 were generated and subjected to pressure overload hypertrophic stimulation. We found that although increased expression of NKA-alpha1 had no protective effect, overexpression of NKA-alpha2 significantly decreased cardiac hypertrophy after pressure overload in mice at 2, 10, and 16 weeks of stimulation. Remarkably, total NKA protein expression and activity were not altered in either of these 2 transgenic models because increased expression of one isoform led to a concomitant decrease in the other endogenous isoform. NKA-alpha2 overexpression but not NKA-alpha1 led to significantly faster removal of bulk Ca2+ from the cytosol in a manner requiring NCX1 activity. Mechanistically, overexpressed NKA-alpha2 showed greater affinity for Na+ compared with NKA-alpha1, leading to more efficient clearance of this ion. Furthermore, overexpression of NKA-alpha2 but not NKA-alpha1 was coupled to a decrease in phospholemman expression and phosphorylation, which would favor greater NKA activity, NCX1 activity, and Ca2+ removal. CONCLUSIONS: Our results suggest that the protective effect produced by increased expression of NKA-alpha2 on the heart after pressure overload is due to more efficient Ca2+ clearance because this isoform of NKA preferentially enhances NCX1 activity compared with NKA-alpha1.

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CRRD Object Information
CRRD ID: 9685471
Created: 2015-01-12
Species: All species
Last Modified: 2015-01-12
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.