Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1

Lin Xu; Christiana S. Kappler; Santhosh K. Mani; Neal R. Shepherd; Ludivine Renaud; Paige Snider; Simon J. Conway; Donald R. Menick

doi:10.1074/jbc.M109.022855

Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1

Lin Xu, Christiana S. Kappler, Santhosh K. Mani, Neal R. Shepherd, Ludivine Renaud, Paige Snider, Simon J. Conway, Donald R. Menick

Cardiac Developmental Biology

Research output: Contribution to journal › Article

10 Scopus citations

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 (US)
Pages (from-to)	27265-27272
Number of pages	8
Journal	Journal of Biological Chemistry
Volume	284
Issue number	40
DOIs	https://doi.org/10.1074/jbc.M109.022855
State	Published - Oct 2 2009

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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Xu, L., Kappler, C. S., Mani, S. K., Shepherd, N. R., Renaud, L., Snider, P., Conway, S. J., & Menick, D. R. (2009). Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1. Journal of Biological Chemistry, 284(40), 27265-27272. https://doi.org/10.1074/jbc.M109.022855

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title = "Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1",

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.",

author = "Lin Xu and Kappler, {Christiana S.} and Mani, {Santhosh K.} and Shepherd, {Neal R.} and Ludivine Renaud and Paige Snider and Conway, {Simon J.} and Menick, {Donald R.}",

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AU - Mani, Santhosh K.

AU - Shepherd, Neal R.

AU - Renaud, Ludivine

AU - Snider, Paige

AU - Conway, Simon J.

AU - Menick, Donald R.

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