UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perturbations of Ca(2+) metabolism are central to the pathogenesis of cardiac hypertrophy. The electrogenic Na(+)-Ca(2+) exchanger mediates a substantial component of transmembrane Ca(2+) movement in cardiac myocytes and is up-regulated in heart failure. However, the role of the exchanger in the pathogenesis of cardiac hypertrophy is poorly understood. Thoracic aortic banding in mice induced 50-60% increases in heart mass and cardiomyocyte size. Despite the absence of myocardial dysfunction, steady-state NCX1 transcript and protein levels were increased to an extent similar to that reported in heart failure. As recent studies indicate that calcineurin is critical to the expression of Na(+)-Ca(2+) exchanger genes, we inhibited calcineurin with cyclosporin. Calcineurin inhibition blunted the increases in NCX1 transcript and protein levels and eliminated the increases in heart mass and cell volume normally associated with pressure overload. To examine the functional significance of these changes, we measured Na(+)-Ca(2+) exchanger current in two independent ways. Surprisingly, exchanger current density was decreased in hypertrophied myocytes, and this down-regulation was eliminated by calcineurin inhibition. Together, these data reveal a role for Na(+)-Ca(2+) exchanger current in the electrical remodeling of hypertrophy and implicate calcineurin signaling therein. In addition, these data suggest the Na(+)-Ca(2+) exchanger is functionally regulated in hypertrophy.
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PMID:Na+-Ca2+ exchanger remodeling in pressure overload cardiac hypertrophy. 1127 89

The cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), Na+/Ca2+ exchanger (NCX1), and ryanodine receptor (RyR2) are proteins involved in the regulation of myocyte calcium. We tested whether exercise training (ET) alters those proteins during development of chronic heart failure (CHF). Ten dogs were chronically instrumented to permit hemodynamic measurements. Five dogs underwent 4 wk of cardiac pacing (210 beats/min for 3 wk and 240 beats/min for the 4th wk), whereas five dogs underwent the same pacing regimen plus daily ET (5.1 +/- 0.3 km/h, 2 h/day). Paced animals developed CHF characterized by hemodynamic abnormalities and reduced ejection fraction. ET preserved resting hemodynamics and ejection fraction. Left ventricular samples were obtained from all dogs and another five normal dogs for mRNA (Northern analysis, band intensities normalized to glyceraldehyde-3-phosphate dehydrogenase) and protein level (Western analysis, band intensities normalized to tubulin) measurements. In failing hearts, SERCA2a was decreased by 33% (P < 0.05) and 65% (P < 0.05) in mRNA and protein level, respectively, compared with normal hearts; there was only an 8.6% reduction in mRNA and a 32% reduction in protein in exercised animals (P < 0.05 from CHF). mRNA expression of NCX1 increased by 44% in paced-only dogs compared with normal (P < 0.05) but only by 22% in trained dogs (P < 0.05 vs. CHF); protein level of NCX1 was elevated in paced-only dogs (71%, P < 0.05) but partially normalized by ET (33%, P < 0.05 from CHF). RyR2 was not altered in any of the dogs. In conclusion, long-term ET may ameliorate cardiac deterioration during development of CHF, in part via normalization of myocardial calcium-handling proteins.
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PMID:Exercise training normalizes altered calcium-handling proteins during development of heart failure. 1189 19

Using Na(+)/Ca(2+) exchanger (NCX1)-deficient mice, the pathophysiological role of Ca(2+) overload via the reverse mode of the Na(+)/Ca(2+) exchanger in ischaemia/reperfusion-induced renal injury was investigated. Since NCX1(-/-) homozygous mice die of heart failure before birth, we utilized NCX1(+/-) heterozygous mice. The ischaemia/reperfusion-induced renal dysfunction in heterozygous mice were significantly attenuated compared with cases in wild-type mice. Also, histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca(2+) deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. The increase in renal endothelin-1 (ET-1) content was significantly greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. We conclude that Ca(2+) overload via the reverse-mode of Na(+)/Ca(2+) exchange, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of ischaemia/reperfusion-induced acute renal failure.
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PMID:Pathophysiological roles of Ca(2+) overload via the Na(+)/Ca(2+) exchanger and endothelin-1 overproduction in ischaemia/reperfusion-induced acute renal failure. 1219 29

Cardiac sodium pumps (Na,K-ATPase) influence cell calcium and contractility by generating the Na+ gradient driving Ca++ extrusion via the Na+/Ca++ exchanger (NCX), and are the receptors for cardiac glycosides such as digitalis which increases cardiac contractility by decreasing the Na+ gradient driving Ca++ extrusion. There are multiple isoforms of the sodium pump expressed in the heart indicating the potential for isoform specific expression patterns, function and regulation. Regarding isoform expression patterns, human heart expresses alpha1, alpha2, alpha3, beta1 and a small amount of beta2. Within the human heart, alpha3, beta1 and NCX levels are 30-50% lower in atria than ventricles, associated with increased sensitivity to inotropic stimulation. Distribution at the cellular level has been studied in the rat heart where both alpha1 and alpha2 are detected in the T-tubules along with NCX. Regarding isoform function, we focussed on human sodium pumps as cardiac glycoside receptors. A study of human sodium pump expressed alone (alpha1) or in combination (alpha1 with alpha2, or alpha1 with alpha2 and alpha3) in their native membranes aimed to determine whether different isoforms had distinct affinities for the cardiac glycoside ouabain by evaluating whether the ouabain binding data were best fit with a single site or two site model. The results indicated that the affinity of these human a subunit isoforms for ouabain is indistinguishable, and that changes in sensitivity to cardiac glycosides during heart failure are likely due to a decrease in the total number of pumps rather than a shift in expression to a more sensitive isoform. Regarding isoform regulation, we hypothesized that a primary decrease in cardiac Na,K-ATPase expression would be associated with a secondary increase in cardiac Na+/Ca++ exchanger expression as a homeostatic mechanism to blunt an increase in cell Ca++ stores (and visa versa with an increase in Na,K-ATPase). Supporting the hypothesis: in a rat model of renovascular hypertension, or after treatment with amiodarone there are 50% decreases in alpha2 levels with 35-40% increases in NCX levels in left ventricle, while in the transition from hypo- to hyperthyroid, there are increases in both alpha1 (2-fold) and alpha2 (8-fold) with decreases in NCX (0.45-fold). In comparison, in transgenic mice overexpressing NCX, there was no secondary change in Na,K-ATPase alpha1 or alpha2 levels indicating that primary changes in NCX do not drive secondary changes in Na,K-ATPase in the heart. This information provides the basis for addressing the significant gaps in our understanding of the physiologic, structural and homeostatic coupling between sodium pump isoforms and Na+/Ca++ exchangers in the heart and how coupling is related to control of cardiac contractility in health and disease.
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PMID:The cardiac sodium pump: structure and function. 1247 29

Using Na+/Ca2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1(-/-) homozygous mice die of heart failure before birth, we used NCX1(+/-) heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca2+ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. Histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca2+ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1(+/+) and NCX1(+/-) acute renal failure mice were improved to the same level. These findings strongly support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.
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PMID:Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ exchanger. 1249 Jun 3

The cardiac-specific sodium-calcium exchanger (NCX1) is a GATA-4 dependent gene that is upregulated during cardiac hypertrophy and heart failure. To date, lack of an appropriate inhibitor of NCX1 and embryonic lethality of NCX1 knockout mice have slowed investigation of the relation between NCX1 upregulation and cardiac hypertrophy. Recently, in vitro studies have shown that cyclosporin A (CSA), a calcineurin inhibitor, significantly downregulated expression of the hypertrophic genes atrial natriuretic factor and beta-myosin heavy chain and protected against cardiac hypertrophy and heart failure in calcineurin overexpressing mice. This suggested that CSA might play an important role in the treatment of hypertrophy and heart failure. In an in vitro model of cardiac hypertrophy, we showed that CSA is a potent inhibitor of NCX1 basal expression and NCX1 promoter activity. Female homozygous transgenic mice that overexpress NCX1 develop heart failure and die prematurely after two or more pregnancies. Others have demonstrated that pressure overloaded wild-type mice treated with CSA do not develop cardiac hypertrophy and downregulate expression of NCX1. We investigated the effect of CSA on NCX1 expression and transverse aortic constriction-induced cardiac hypertrophy in NCX1 overexpressing mice. We found that CSA blunted these responses.
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PMID:Cyclosporin A regulates sodium-calcium exchanger (NCX1) gene expression in vitro and cardiac hypertrophy in NCX1 transgenic mice. 1250 68

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and nephron cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. Recently, the benzyloxyphenyl derivatives KB-R7943, SEA0400, and SN-6 have been developed as selective NCX inhibitors. Currently, SEA0400 is the most potent and selective inhibitor. These inhibitors possess different isoform-selectivities, although they have similar properties, such as Ca2+ influx mode-selectivity and I1 inactivation-dependence. Recent site-directed mutagenesis has revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Moreover, such inhibitors may have therapeutic potential as a new remedy for ischemic disease, arrhythmias, heart failure, and hypertension.
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PMID:Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors. 1535 84

Serum response factor (SRF) is a transcription factor required for the regulation of genes important for cardiac structure and function. Notably, the "fetal gene expression profile" that is characteristic of cardiac hypertrophy consists of genes known to be regulated by SRF. Transgenic animal studies suggest that cardiac-specific overexpression of SRF induces this pattern of hypertrophic genes and subsequently causes the progression of pathologic adaptations. Furthermore, studies examining cardiac tissues from patients with severe heart failure indicate significant alterations in SRF expression that correspond with alterations in expression of SRF-dependent genes. Based on these observations, it has been postulated that SRF may be critical for stimulating pathologic gene expression at the onset of hypertrophic adaptation. To address the role of SRF in cardiac hypertrophy we investigated whether SRF is necessary and sufficient for the expression of genes associated with the hypertrophic response. We used isolated cardiomyocytes from both neonatal rats, and transgenic mice containing floxed SRF alleles, to examine cardiac gene expression in response to overexpression and absence of SRF. Using this approach, we demonstrate that SRF is required for the induction of atrial naturetic factor (ANF), c-fos, NCX1, BNP, alpha-actins, alpha-myosin heavy chain, and beta-myosin heavy chain genes. However, overexpression of exogenous SRF in isolated cardiomyocytes is only sufficient to induce NCX1 and alpha-myosin heavy chain. These results indicate that SRF is critical for the regulation and induction of genes associated with the progression of pathologic cardiac hypertrophy, however, the pattern of genes induced by overexpression of SRF in isolated cardiomyocytes is different from those genes expressed in hypertrophic transgenic hearts. This suggests that SRF-dependent gene expression is modulated in a complex manner by in vivo physiologic systems prior to and during heart failure as the organism adapts to cardiac stress.
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PMID:SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy. 1595 Sep 86

Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function +/-1 microM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca](i)) dependence of NCX function from the decay rate of caffeine-induced [Ca](i) transients. Second, we measured caffeine-induced [Ca](i) and inward I(NCX) simultaneously (perforated patch voltage clamp), to measure directly the [Ca](i) dependence of NCX rate. Third, using whole cell ruptured patch with [Ca](i) heavily buffered to 100 nM, [Na](i)=10 mM, and I(Ca), SR Ca release and Na/K pump all blocked, we recorded I(NCX) ramps at 37 degrees C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca](i) and [Na](i).
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PMID:Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes. 1624 49

Calcium entry into myocytes drives contraction of the embryonic heart. To prepare for the next contraction, myocytes must extrude calcium from intracellular space via the Na+/Ca2+ exchanger (NCX1) or sequester it into the sarcoplasmic reticulum, via the sarcoplasmic reticulum Ca2+-ATPase2 (SERCA2). In mammals, defective calcium extrusion correlates with increased intracellular calcium levels and may be relevant to heart failure and sarcoplasmic dysfunction in adults. We report here that mutation of the cardiac-specific NCX1 (NCX1h) gene causes embryonic lethal cardiac arrhythmia in zebrafish tremblor (tre) embryos. The tre ventricle is nearly silent, whereas the atrium manifests a variety of arrhythmias including fibrillation. Calcium extrusion defects in tre mutants correlate with severe disruptions in sarcomere assembly, whereas mutations in the L-type calcium channel that abort calcium entry do not produce this phenotype. Knockdown of SERCA2 activity by morpholino-mediated translational inhibition or pharmacological inhibition causes embryonic lethality due to defects in cardiac contractility and morphology but, in contrast to tre mutation, does not produce arrhythmia. Analysis of intracellular calcium levels indicates that homozygous tre embryos develop calcium overload, which may contribute to the degeneration of cardiac function in this mutant. Thus, the inhibition of NCX1h versus SERCA2 activity differentially affects the pathophysiology of rhythm in the developing heart and suggests that relative levels of NCX1 and SERCA2 function are essential for normal development.
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PMID:Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts. 1631 82

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