Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger.

Abstract

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.

METHODS AND 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.

• Authors: Kenneth P Roos, Maria C Jordan, Michael C Fishbein, Matthew R Ritter, Martin Friedlander, Helen C Chang, Paymon Rahgozar, Tieyan Han, Alejandro J Garcia, W Robb Maclellan, Robert S Ross, Kenneth D Philipson
• Journal: Journal of cardiac failure (J Card Fail) Vol. 13 Issue 4 Pg. 318-29 (May 2007) ISSN: 1532-8414 [Electronic] United States
• PMID: 17517353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NCX1 protein, mouse
• Sodium-Calcium Exchanger

Topics

• Animals
• Animals, Genetically Modified
• Cardiomegaly (diagnostic imaging, genetics, metabolism)
• Disease Models, Animal
• Female
• Gene Expression (genetics)
• Gene Expression Profiling (methods)
• Heart Failure (diagnostic imaging, genetics, metabolism)
• Male
• Mice
• Phenotype
• Sodium-Calcium Exchanger (genetics, metabolism)
• Ultrasonography