Dysfunction of ouabain-induced cardiac contractility in mice with heart-specific ablation of Na,K-ATPase beta1-subunit.
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.
Barwe
Sonali P
SP
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Rockland Center One, 1701 Rockland Road, Wilmington, DE 19803, USA.
Jordan
Maria C
MC
Skay
Anna
A
Inge
Landon
L
Rajasekaran
Sigrid A
SA
Wolle
Daniel
D
Johnson
Christina L
CL
Neco
Patricia
P
Fang
Kun
K
Rozengurt
Nora
N
Goldhaber
Joshua I
JI
Roos
Kenneth P
KP
Rajasekaran
Ayyappan K
AK
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*
C503552:Atp1b1 protein, mouse; C499849:NCX1 protein, mouse; D021122:Protein Subunits; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase
Am J Cardiol. 1988 Jun 1;61(15):1312-5
3376892
Mol Cell. 1999 May;3(5):555-63
10360172
J Cell Biol. 1990 Jan;110(1):165-74
1688561
Circ Res. 2002 Feb 22;90(3):305-8
11861419
Basic Res Cardiol. 2002;97 Suppl 1:I19-24
12479229
Am J Physiol. 1985 Nov;249(5 Pt 2):H1056-60
2998207
Am J Physiol. 1996 Apr;270(4 Pt 1):C1221-7
8928749
Circulation. 1999 Apr 27;99(16):2105-12
10217649
Semin Nephrol. 2005 Sep;25(5):328-34
16139688
Am J Physiol Renal Physiol. 2006 Feb;290(2):F241-50
16403837
J Am Assoc Lab Anim Sci. 2006 Jul;45(4):8-13
16884172
Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H584-5
18178717
Mol Biol Cell. 2004 Jul;15(7):3224-32
15133131
Ann N Y Acad Sci. 1996 Apr 15;779:318-35
8659845
J Cell Biol. 1994 Nov;127(3):835-45
7525597
J Card Fail. 2007 May;13(4):318-29
17517353
J Biol Chem. 1998 Jan 9;273(2):1252-6
9422794
Front Biosci (Landmark Ed). 2009 Jan 01;14:2130-48
19273189
Circ Res. 2004 Sep 17;95(6):604-11
15308581
Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1982-8
15563542
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11476-81
12169672
Am J Cardiol. 1999 Feb 1;83(3):396-9
10072231
Mol Biol Cell. 2005 Mar;16(3):1082-94
15616195
Cardiovasc Res. 2003 Mar 15;57(4):913-20
12650869
Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H613-21
18065526
J Biol Chem. 2004 Dec 24;279(52):54053-61
15485817
J Biol Chem. 2003 Dec 26;278(52):53026-34
14559919
J Neurosci. 1998 Nov 15;18(22):9192-203
9801359
Development. 1998 May;125(10):1943-9
9550726
Annu Rev Physiol. 2006;68:431-59
16460279
J Mol Biol. 2007 Jan 19;365(3):706-14
17078968
Am J Physiol Cell Physiol. 2006 Oct;291(4):C569-78
16624992