Chronic inhibition of NCX1 by KB-R7943 induces up-regulation of Ncx1 gene expression via p38 activation, demonstrating that NCX1 can regulate activity-dependent signal transduction.
Chronic NCX1 inhibition may trigger compensatory up-regulation in animals; leaves open translational relevance to human cardiac therapies.
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.
No takes yet. Share an insight, caveat, or question.
Xu et al. (2009) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: