Na+-Ca2+ exchanger remodeling in pressure overload cardiac hypertrophy.
Perturbations of Ca(2+) metabolism are central to the pathogenesis of cardiac hypertrophy. The electrogenic Na(+)-Ca(2+) exchanger mediates a substantial component of transmembrane Ca(2+) 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(+)-Ca(2+) 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(+)-Ca(2+) 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(+)-Ca(2+) exchanger current in the electrical remodeling of hypertrophy and implicate calcineurin signaling therein. In addition, these data suggest the Na(+)-Ca(2+) exchanger is functionally regulated in hypertrophy.
Wang
Z
Z
Department of Internal Medicine, the Interdisciplinary Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Nolan
B
B
Kutschke
W
W
Hill
J A
JA
D000200:Action Potentials; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1