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, [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.The cardiac NCX1 (Na ϩ -Ca 2ϩ exchanger) plays a critical role in maintaining the balance of Ca 2ϩ flux across the sarcolemmal membrane in excitation-contraction coupling (1). Cardiac muscle contracts in response to the rise in [Ca 2ϩ ] i , which is released from the sarcoplasmic reticulum (SR) 5 and from influx across the sarcolemma through voltage-sensitive channels. SR Ca 2ϩ -ATPase recycles Ca 2ϩ from the cytosol into the lumen of the SR, and NCX1 mediates the movement of [Ca 2ϩ ] i across the sarcolemma to the extracellular space. NCX1 transports ϳ28% of the cytosolic Ca 2ϩ during a contractionrelaxation cycle in large animals and humans, with 70% being reaccumulated in the SR (via SR Ca 2ϩ -ATPase) (2-4). Alterations in any of the activities associated with this complex process causes a corresponding change in the amount of Ca 2ϩ released from the SR, and the resulting force of cardiac contraction.The exchanger is regulated at the transcriptional level in animal models of cardiac hypertrophy (5, 6) and ischemia and failure (7-12). Importantly, both NCX1 mRNA and protein levels are significantly up-regulated in human end-stage heart failure (13-16). The diastolic performance of failing human myocardium correlates inversely with protein levels of NCX1 (17), and up-regulation of Ncx1 alone contributes directly to impaired SR loading and contractile dysfunction (18,19). Ventricular tachycardia, a precursor to ventricular fibrillation and a major cause of sudden death in heart failure, has also been linked to up-regulation of NCX1. NCX1 up-regulation results in a greater potential for delayed after depolarizations, which are major initiators of ventricular tachycardia (9, 20). In addition, Ca 2ϩ loading, which is one of the major causes of myocardial damage following ischemia-reperfusion, is mediated via reverse mode NCX1. All three benzyloxyphenyl NCX inhibitors, KB-R7943, SN-6, and SEA-0400, have been reported to confe...

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