Dysfunction of ouabain-induced cardiac contractility in mice with heart-specific ablation of Na,K-ATPase beta1-subunit

J Mol Cell Cardiol. 2009 Oct;47(4):552-60. doi: 10.1016/j.yjmcc.2009.07.018. Epub 2009 Aug 15.


Na,K-ATPase is composed of two essential alpha- and beta-subunits, both of which have multiple isoforms. Evidence indicates that the Na,K-ATPase enzymatic activity as well as its alpha(1), alpha(3) and beta(1) isoforms are reduced in the failing human heart. The catalytic alpha-subunit is the receptor for cardiac glycosides such as digitalis, used for the treatment of congestive heart failure. The role of the Na,K-ATPase beta(1)-subunit (Na,K-beta(1)) in cardiac function is not known. We used Cre/loxP technology to inactivate the Na,K-beta(1) gene exclusively in the ventricular cardiomyocytes. Animals with homozygous Na,K-beta(1) gene excision were born at the expected Mendelian ratio, grew into adulthood, and appeared to be healthy until 10 months of age. At 13-14 months, these mice had 13% higher heart/body weight ratios, and reduced contractility as revealed by echocardiography compared to their wild-type (WT) littermates. Pressure overload by transverse aortic constriction (TAC) in younger mice, resulted in compensated hypertrophy in WT mice, but decompensation in the Na,K-beta(1) KO mice. The young KO survivors of TAC exhibited decreased contractile function and mimicked the effects of the Na,K-beta(1) KO in older mice. Further, we show that intact hearts of Na,K-beta(1) KO anesthetized mice as well as isolated cardiomyocytes were insensitive to ouabain-induced positive inotropy. This insensitivity was associated with a reduction in NCX1, one of the proteins involved in regulating cardiac contractility. In conclusion, our results demonstrate that Na,K-beta(1) plays an essential role in regulating cardiac contractility and that its loss is associated with significant pathophysiology of the heart.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Animals
  • Calcium Signaling / drug effects
  • Cardiomegaly / enzymology
  • Cardiomegaly / physiopathology
  • Cell Separation
  • Gene Deletion*
  • Heart Function Tests
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Myocardial Contraction / drug effects*
  • Myocardium / enzymology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Organ Specificity / drug effects
  • Ouabain / pharmacology*
  • Pressure
  • Protein Subunits / metabolism*
  • Sodium-Calcium Exchanger / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism*


  • Atp1b1 protein, mouse
  • NCX1 protein, mouse
  • Protein Subunits
  • Sodium-Calcium Exchanger
  • Ouabain
  • Sodium-Potassium-Exchanging ATPase