The Exchanger and Cardiac Hypertrophy<sup>a</sup>

Menick, Donald R.; Barnes, Kimberly V.; Thacker, Usha F.; Dawson, Myra; McDERMOTT, Diane E.; Rozich, John D.; Kent, Robert L.; Cooper, George

doi:10.1111/j.1749-6632.1996.tb44823.x

Cited by 29 publications

(26 citation statements)

References 16 publications

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“…Both NCX1 mRNA and protein levels respond to various signals (18,28). Although much research has focused on the mechanism of regulation of NCX1 at the posttranslational level, few studies have directly addressed the regulation of NCX1 expression at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

“…Within the enhancers there are NF-Y, SRF, and NF-1 elements that are capable of enhancer activity (7,11). AP-1 sites present within the proximal NCX1 promoter provide sites that may mediate c-fos-induced responses to hypertrophy (28) and stretch (18).…”

Section: Discussionmentioning

confidence: 99%

“…In the feline model of acute right ventricular hypertrophy, NCX1 mRNA levels are upregulated following pressure overload (28). An increase in NCX1 mRNA expression was also observed in cultured cardiac myocytes following ␣-adrenergic stimulation by phenylephrine or exposure to veratridine (28). NCX1 mRNA and protein levels decline following birth and during normal cardiac development in rabbit and rat heart (4).…”

mentioning

confidence: 91%

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Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene

Nicholas

Yang

Lee

et al. 1998

American Journal of Physiology-Heart and Circulatory Physiology

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Lytton. Alternative promoters and cardiac muscle cellspecific expression of the Na ϩ /Ca 2ϩ exchanger gene. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H217-H232, 1998.-Many studies have investigated the regulation of the Na ϩ / Ca 2ϩ exchanger, NCX1, but limited data exist on transcriptional regulation of the NCX1 gene. We have identified the transcription start sites of three tissue-specific alternative promoters of NCX1 transcripts from rat heart, kidney, and brain. We have characterized the cardiac NCX1 promoter, from which the most abundant quantities of NCX1 transcripts are expressed. Transfection of primary cardiac myocytes, CHO cells, and COS-7 cells with overlapping genomic DNA fragments spanning the NCX1 cardiac transcription start site has uncovered a cardiac cell-specific minimum promoter from Ϫ137 to ϩ85. The cardiac NCX1 promoter is TATA-less but has putative binding sites for cardiac-specific GATA factors, an E box, and an Inr as well as multiple active enhancers. The kidney NCX1 promoter has a typical TATA box and binding sites for several tissue-specific factors. The brain NCX1 promoter is very GC-rich and possesses several Sp-1 binding sites consistent with its ubiquitous expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

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Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene

Nicholas

Yang

Lee

et al. 1998

American Journal of Physiology-Heart and Circulatory Physiology

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“…The exchanger is regulated at the transcriptional level in animal models of cardiac hypertrophy (5,6) and ischemia and failure (7)(8)(9)(10)(11)(12). Importantly, both NCX1 mRNA and protein levels are significantly up-regulated in human end-stage heart failure (13)(14)(15)(16).…”

mentioning

confidence: 99%

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

Kappler

Mani

et al. 2009

Journal of Biological Chemistry

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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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“…4,8,9,22) However, protein data on the expression of the Na,Ca-exchanger in heart failure and related disease states as well as functional data are controversial: Both increased expression of the Na,Ca-exchanger protein 10,23,24) and increased activity of the Na,Ca-exchanger 20,25,26) have been measured in heart failure in humans and other species. In pacing-induced heart failure in rabbit, an increase in Na,Ca-exchanger protein was not accompanied by an enhanced activity.…”

Section: Discussionmentioning

confidence: 99%

Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

et al. 2007

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SUMMARYThe present study aimed to investigate the hypothesis that the function of the Na,Caexchanger (NCX) is of higher importance for contractility and Ca 2+-homeostasis in left ventricle from terminally failing than from nonfailing human hearts.The effect of decreasing extracellular [Na] e (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na] e has previously been shown to increase contractility in vitro secondary to a decreased Ca 2+ -extrusion by the NCX. In addition, the NCX activity was measured as Na + -dependent 45 Ca 2+ -uptake into isolated myocardial vesicles as a function of time and Ca 2+ -concentration (DCM n = 8, NF n = 8). Decreasing [Na] e enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na] e than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T 1/2 : DCM 2.4 ± 0.3 s versus NF 2.5 ± 0.3 s) and as a function of Ca These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca 2+ -ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca 2+ -affinity of the Na,Caexchanger in isolated vesicles was unchanged, we propose that alterations in Ca 2+ -and Na + -homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na + , K + -ATPase) or the prolonged action potential are the reason for this observation. (Int Heart J 2007; 48: 755-766)

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The Exchanger and Cardiac Hypertrophy^a

Cited by 29 publications

References 16 publications

Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene

Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene

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

Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

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The Exchanger and Cardiac Hypertrophya

Cited by 29 publications

References 16 publications

Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+exchanger gene

Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+exchanger gene

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

Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

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The Exchanger and Cardiac Hypertrophy^a

Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene

Alternative promoters and cardiac muscle cell-specific expression of the Na⁺/Ca²⁺exchanger gene