title: Dysfunction of ouabain-induced cardiac contractility in mice with heart-specific ablation of Na,K-ATPase beta1-subunit.
abstract: 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.
authors.affiliation: Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Rockland Center One, 1701 Rockland Road, Wilmington, DE 19803, USA.
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Barwe
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.forename: Anna
authors.initials: A
authors.lastname: Skay
authors.forename: Landon
authors.initials: L
authors.lastname: Inge
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Rajasekaran
authors.forename: Daniel
authors.initials: D
authors.lastname: Wolle
authors.forename: Christina L
authors.initials: CL
authors.lastname: Johnson
authors.forename: Patricia
authors.initials: P
authors.lastname: Neco
authors.forename: Kun
authors.initials: K
authors.lastname: Fang
authors.forename: Nora
authors.initials: N
authors.lastname: Rozengurt
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology; D002469:Cell Separation; D017353:Gene Deletion; D006334:Heart Function Tests; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology*; D011312:Pressure; D021122:Protein Subunits / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: C503552:Atp1b1 protein, mouse; C499849:NCX1 protein, mouse; D021122:Protein Subunits; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase
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