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 Conway, Donald R. Menick

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 languageEnglish
Pages (from-to)27265-27272
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
StatePublished - Oct 2 2009

Fingerprint

Up-Regulation
Heart Failure
Sodium-Calcium Exchanger
Gene expression
Sarcolemma
Gene Expression Regulation
Chemical activation
Cardiac Myocytes
Reperfusion
Signal Transduction
Signal transduction
Ischemia
Animal Models
Calcium
Gene Expression
Membranes
2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
Animals

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Xu, L., Kappler, C. S., Mani, S. K., Shepherd, N. R., Renaud, L., Snider, P., ... 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

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 journalArticle

Xu, L, Kappler, CS, Mani, SK, Shepherd, NR, Renaud, L, Snider, P, Conway, S & Menick, DR 2009, 'Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1', Journal of Biological Chemistry, vol. 284, no. 40, pp. 27265-27272. https://doi.org/10.1074/jbc.M109.022855
Xu L, Kappler CS, Mani SK, Shepherd NR, Renaud L, Snider P et al. Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1. Journal of Biological Chemistry. 2009 Oct 2;284(40):27265-27272. https://doi.org/10.1074/jbc.M109.022855
Xu, Lin ; Kappler, Christiana S. ; Mani, Santhosh K. ; Shepherd, Neal R. ; Renaud, Ludivine ; Snider, Paige ; Conway, Simon ; Menick, Donald R. / Chronic administration of KB-R7943 induces up-regulation of cardiac NCX1. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 40. pp. 27265-27272.
@article{fe86ccc5e86e429f8d9228c2f9188340,
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 Simon Conway and Menick, {Donald R.}",
year = "2009",
month = "10",
day = "2",
doi = "10.1074/jbc.M109.022855",
language = "English",
volume = "284",
pages = "27265--27272",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=70350444710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350444710&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.022855

DO - 10.1074/jbc.M109.022855

M3 - Article

C2 - 19661061

AN - SCOPUS:70350444710

VL - 284

SP - 27265

EP - 27272

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -