Abstract
Perturbations of Ca2+ metabolism are central to the pathogenesis of cardiac hypertrophy. The electrogenic Na+-Ca 2+ 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17706-17711 |
| Number of pages | 6 |
| Journal | Journal of Biological Chemistry |
| Volume | 276 |
| Issue number | 21 |
| DOIs | |
| State | Published - Jan 25 2001 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy. / Wang, Zhengyi; Nolan, Bridgid; Kutschke, William; Hill, Joseph A.
In: Journal of Biological Chemistry, Vol. 276, No. 21, 25.01.2001, p. 17706-17711.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy
AU - Wang, Zhengyi
AU - Nolan, Bridgid
AU - Kutschke, William
AU - Hill, Joseph A
PY - 2001/1/25
Y1 - 2001/1/25
N2 - Perturbations of Ca2+ metabolism are central to the pathogenesis of cardiac hypertrophy. The electrogenic Na+-Ca 2+ 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.
AB - Perturbations of Ca2+ metabolism are central to the pathogenesis of cardiac hypertrophy. The electrogenic Na+-Ca 2+ 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.
UR - http://www.scopus.com/inward/record.url?scp=0035947592&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035947592&partnerID=8YFLogxK
U2 - 10.1074/jbc.M100544200
DO - 10.1074/jbc.M100544200
M3 - Article
C2 - 11279089
AN - SCOPUS:0035947592
VL - 276
SP - 17706
EP - 17711
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 21
ER -