Document Detail


Mice expressing ouabain-sensitive α1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy.
MedLine Citation:
PMID:  20952666     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Na,K-ATPase is a ubiquitous transmembrane pump and a specific receptor for cardiac glycosides such as ouabain and digoxin, which are used in the management of congestive heart failure (CHF). A potential role for these so-called endogenous cardiotonic steroids (CS) has been explored, and it has become apparent that such compounds are elevated and may play an important role in a variety of physiological and pathophysiological conditions such as hypertension and CHF. Recent evidence suggests that the Na,K-ATPase may act as a signal transducer upon CS binding and induce nonproliferative cardiac growth, implicating a role for endogenous CS in the development of cardiac hypertrophy and progressive failure of the heart. In the present study, we tested whether hypertrophic responses to pressure overload would be altered in mutant mice that specifically express ouabain-sensitive or ouabain-resistant α1- and α2-Na,K-ATPase subunits, as follows: α1-resistant, α2-resistant (α1(R/R)α2(R/R)); α1-sensitive, α2-resistant (α1(S/S)α2(R/R)); and α1-resistant, α2-sensitive (α1(R/R)α2(S/S), wild-type). In α1(S/S)α2(R/R) mice, pressure overload by transverse aortic coarctation induced severe left ventricular (LV) hypertrophy with extensive perivascular and replacement fibrosis at only 4 wk. Responses in α1(R/R)α2(S/S) and α1(R/R)α2(R/R) mice were comparatively mild. Mutant α1(S/S)α2(R/R) mice also had LV dilatation and depressed LV systolic contractile function by 4 wk of pressure overload. In separate experiments, chronic Digibind treatment prevented the rapid progression of cardiac hypertrophy and fibrosis in α1(S/S)α2(R/R) mice. These data demonstrate that mice with a ouabain-sensitive α1-Na,K-ATPase subunit have a dramatic susceptibility to the development of cardiac hypertrophy, and failure from LV pressure overload and provide evidence for the involvement of endogenous CS in this process.
Authors:
Arshani N Wansapura; Valerie M Lasko; Jerry B Lingrel; John N Lorenz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-15
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  300     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-04     Completed Date:  2011-01-28     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H347-55     Citation Subset:  IM    
Affiliation:
Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0576, USA.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Blotting, Western
Cardiomegaly / genetics,  metabolism*
Echocardiography
Genotype
Hemodynamics
Mice
Mice, Transgenic
Ouabain / metabolism*
Protein Isoforms / genetics,  metabolism
Sodium-Potassium-Exchanging ATPase / genetics,  metabolism*
Ventricular Function, Left / genetics
Grant Support
ID/Acronym/Agency:
DK57552/DK/NIDDK NIH HHS; HL28573/HL/NHLBI NIH HHS; HL66062/HL/NHLBI NIH HHS; R01 HL028573-27/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Protein Isoforms; 630-60-4/Ouabain; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase
Comments/Corrections
Comment In:
Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H29-30   [PMID:  20971770 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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