Abstract
The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1-/- mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1-/- mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca2+]i. Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of "activity-dependent signal transduction" leading to changes in gene expression.
| Original language | English |
|---|---|
| Pages (from-to) | 27265-27272 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 284 |
| Issue number | 40 |
| DOIs | |
| State | Published - Oct 2 2009 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
- Medicine(all)
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Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1. / Xu, Lin; Kappler, Christiana S.; Mani, Santhosh K.; Shepherd, Neal R.; Renaud, Ludivine; Snider, Paige; Conway, Simon; Menick, Donald R.
In: Journal of Biological Chemistry, Vol. 284, No. 40, 02.10.2009, p. 27265-27272.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1
AU - Xu, Lin
AU - Kappler, Christiana S.
AU - Mani, Santhosh K.
AU - Shepherd, Neal R.
AU - Renaud, Ludivine
AU - Snider, Paige
AU - Conway, Simon
AU - Menick, Donald R.
PY - 2009/10/2
Y1 - 2009/10/2
N2 - The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1-/- mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1-/- mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca2+]i. Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of "activity-dependent signal transduction" leading to changes in gene expression.
AB - The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1-/- mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1-/- mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca2+]i. Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of "activity-dependent signal transduction" leading to changes in gene expression.
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U2 - 10.1074/jbc.M109.022855
DO - 10.1074/jbc.M109.022855
M3 - Article
VL - 284
SP - 27265
EP - 27272
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 40
ER -