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J. Biol. Chem., Vol. 276, Issue 21, 17706-17711, May 25, 2001
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From the Departments of Perturbations of Ca2+
metabolism are central to the pathogenesis of cardiac hypertrophy. The
electrogenic Na+-Ca2+ exchanger mediates a
substantial component of transmembrane Ca2+ movement in
cardiac myocytes and is up-regulated in heart failure. However, the
role of the exchanger in the pathogenesis of cardiac hypertrophy is
poorly understood. Thoracic aortic banding in mice induced 50-60%
increases in heart mass and cardiomyocyte size. Despite the absence of
myocardial dysfunction, steady-state NCX1 transcript and protein levels
were increased to an extent similar to that reported in heart failure.
As recent studies indicate that calcineurin is critical to the
expression of Na+-Ca2+ exchanger genes, we
inhibited calcineurin with cyclosporin. Calcineurin inhibition blunted
the increases in NCX1 transcript and protein levels and eliminated the
increases in heart mass and cell volume normally associated with
pressure overload. To examine the functional significance of these
changes, we measured Na+-Ca2+ exchanger current
in two independent ways. Surprisingly, exchanger current density was
decreased in hypertrophied myocytes, and this down-regulation was
eliminated by calcineurin inhibition. Together, these data reveal a
role for Na+-Ca2+ exchanger current in the
electrical remodeling of hypertrophy and implicate calcineurin
signaling therein. In addition, these data suggest the
Na+-Ca2+ exchanger is functionally regulated in hypertrophy.
Na+-Ca2+ Exchanger Remodeling in Pressure
Overload Cardiac Hypertrophy*
§,, and¶
**
Internal Medicine and
Pharmacology, the ** Interdisciplinary Graduate Program in
Molecular Biology, University of Iowa College of Medicine, and the
¶ Department of Veterans Affairs, Iowa City, Iowa 52242
*
This work was supported by grants from the Donald W. Reynolds Cardiovascular Clinical Research Center, Roy J. Carver
Charitable Trust, Departent of Veterans Affairs, American Heart
Association-Heartland Affiliate, and National Institutes of Health
Grant HL-03908.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Cardiovascular
Div., University of Iowa College of Medicine, E318GH, UIHC, 200 Hawkins
Dr., Iowa City, IA 52242-1081. Tel.: 319-384-9829; Fax: 319-353-6343;
E-mail: joseph-hill@uiowa.edu.
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