Chronic Administration of KB-R7943 Induces Up-regulation of Cardiac NCX1

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Aug 8

PMID 19661061

Citations 10

Authors

Lin Xu

Christiana S Kappler

Santhosh K Mani

Neal R Shepherd

Ludivine Renaud

Paige Snider

Simon J Conway

Donald R Menick

Affiliations

Soon will be listed here.

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, [Ca(2+)](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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