Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger.
BACKGROUND
The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. Because heart failure is associated with increased expression of NCX1, heterozygous (HET) and homozygous (HOM) transgenic mice overexpressing NCX1 were developed and evaluated.


RESULTS
The NCX1 transgenic mice display 2.3-fold (HET) and 3.1-fold (HOM) increases in exchanger activity from wild-type (WT) mice. Functional information was obtained by echocardiography and catheterizations before and after hemodynamic stress from pregnancy, treadmill exercise or transaortic constriction (TAC). HET and HOM mice exhibited hypertrophy and blunted responses with beta-adrenergic stimulation. Postpartum mice from all groups were hypertrophied, but only the HOM mice exhibited premature death from heart failure. HOM mice became exercise intolerant after 6 weeks of daily treadmill running. After 21 days TAC, HET, and HOM mice exhibited significant contractile dysfunction and 15% to 40% mortality with clinical evidence of heart failure.


CONCLUSIONS
Hemodynamic stress results in a compensated hypertrophy in WT mice, but NCX1 transgenic mice exhibit decreased contractile function and heart failure in proportion to their level of NCX1 expression. Thus exchanger overexpression in mice leads to abnormal calcium handling and a decompensatory transition to heart failure with stress.
Roos
Kenneth P
KP
Department of Physiology, The Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1751, USA.
Jordan
Maria C
MC
Fishbein
Michael C
MC
Ritter
Matthew R
MR
Friedlander
Martin
M
Chang
Helen C
HC
Rahgozar
Paymon
P
Han
Tieyan
T
Garcia
Alejandro J
AJ
Maclellan
W Robb
WR
Ross
Robert S
RS
Philipson
Kenneth D
KD
D000818:Animals; D030801:Animals, Genetically Modified; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D010641:Phenotype; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography
C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger