Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure.

Studer, Rebecca K.; Reinecke, Hans; Bilger, Johannes; Eschenhagen, Thomas; Böhm, Michael; Hasenfuß, Gerd; Just, Hanjörg; Holtz, J.; Drexler, Helmut

doi:10.1161/01.res.75.3.443

Cited by 537 publications

(310 citation statements)

References 46 publications

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“…For example, NCX1 protein expression has been reported to decrease (71), increase (22,61,68), or remain unchanged (22,57) in HF. Although it is generally thought that SERCA2 mRNA levels decrease in CHF (3,11,29,55,61,68), no consensus exists in regard to protein levels, with some studies finding no change (29, 38 -40, 55, 56) and others a decrease (11,21,34,61,68) in expression. The same ambiguity is true with respect to the SERCA2 regulatory protein PLB.…”

Section: Discussionmentioning

confidence: 99%

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Emter

McCune²,

Sparagna³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. Am J Physiol Heart Circ Physiol 289: H2030 -H2038, 2005. First published July 1, 2005; doi:10.1152/ajpheart.00526.2005.-Data regarding the effectiveness of chronic exercise training in improving survival in patients with congestive heart failure (CHF) are inconclusive. Therefore, we conducted a study to determine the effect of exercise training on survival in a well-defined animal model of heart failure (HF), using the lean male spontaneously hypertensive HF (SHHF) rat. In this model, animals typically present with decompensated, dilated HF between ϳ18 and 23 mo of age. SHHF rats were assigned to sedentary or exercise-trained groups at 9 and 16 mo of age. Exercise training consisted of 6 mo of low-intensity treadmill running. Exercise training delayed the onset of overt HF and improved survival (P Ͻ 0.01), independent of any effects on the hypertensive status of the rats. Training delayed the myosin heavy chain (MyHC) isoform shift from ␣-to ␤-MyHC that was seen in sedentary animals that developed HF. Exercise was associated with a concurrent increase in cardiomyocyte length (Ϸ6%), width, and area and prevented the increase in the length-to-width ratio seen in sedentary animals in HF. The increases in proteinuria, plasma atrial natriuretic peptide, and serum leptin levels observed in rats with HF were suppressed by low-intensity exercise training. No significant alterations in sarco (endo)plasmic reticulum Ca 2ϩ ATPase, phospholamban, or Na ϩ / Ca 2ϩ exchanger protein expression were found in response to training. Our results indicate that 6 mo of low-intensity exercise training delays the onset of decompensated HF and improves survival in the male SHHF rat. Similarly, exercise intervention prevented or suppressed alterations in several key variables that normally occur with the development of overt CHF. These data support the idea that exercise may be a useful and inexpensive intervention in the treatment of HF. myosin heavy chain; proteinuria; cardiomyocyte morphology; atrial natriuretic peptide; leptin HEART DISEASE is a leading cause of death among men and women in Western industrialized societies. Cardiovascular disease (CVD) currently affects over 70 million Americans, 65 million of which are estimated to have high blood pressure and nearly 5 million are diagnosed with congestive heart failure (CHF) (2). With the diagnosis of CHF, life expectancy decreases dramatically and chances of survival decrease with 70 -80% of patients dying within 8 yr (2). Although chronic exercise training has clearly been shown to be beneficial in attenuating risk factors for CVD, including high blood pressure and cholesterol levels, insulin resistance, and obesity (9,14,53,58), the utility of exercise as a clinical intervention for patients with developing CHF is less clear. Currently, there is a lack of clarity regarding the efficacy of chronic exercise training as a treatment and in reducing mortali...

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Section: Discussionmentioning

confidence: 99%

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Emter

McCune²,

Sparagna³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184], lead to a smaller and more dyssynchronous SR Ca 2+ release during an AP, resulting in slower rates of increase and decay of [Ca 2+ ] c , but higher diastolic [Ca 2+ ] c compared to normal cardiac myocytes [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190], since pronounced forward mode I NCX may maintain diastolic function [85] by removing Ca 2+ to the extracellular space. On the other hand, this pronounced forward mode I NCX may further aggravate SR Ca 2+ depletion, since inhibition of I NCX with an inhibitor peptide (XIP [118]) restored SR Ca 2+ load in failing myocytes [91].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…The expression level of NCX1 is modulated during development (3,4) and under pathological conditions (5)(6)(7)(8)(9). The Na ϩ /Ca 2ϩ exchanger activity has been shown to be affected by the ions that it transports (Na ϩ and Ca 2ϩ ) (10 -13), by protons (14,15), by phosphatidylinositol 4,5-bisphosphate in the membrane (16), and by exogenous agents including intracellular application of an inhibitor peptide (XIP) (17).…”

mentioning

confidence: 99%

Sodium/Calcium Exchanger (NCX1) Macromolecular Complex

Schulze

Muqhal

Lederer

et al. 2003

Journal of Biological Chemistry

122

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The sodium-calcium exchanger, NCX1, is a ubiquitously expressed membrane protein essential in calcium homeostasis for many cells including those in mammalian heart and brain. The function of NCX1 depends on subcellular ("local") factors, the phosphorylation state of NCX1, and the subcellular location of NCX1 within the cell. Here we investigate the molecular organization of NCX1 within the cardiac myocyte. We show that NCX1 is dynamically phosphorylated by protein kinase A (PKA)-dependent phosphorylation in vitro. We also provide evidence that the regulation of this phosphorylation is attributed to the existence of an NCX1 macromolecular complex. Specifically, we show that the macromolecular complex includes both the catalytic and regulatory subunits of PKA. However, only the RI regulatory subunit is found in this macromolecular complex, not RII. Other critical regulatory enzymes are also associated with NCX1, including protein kinase C (PKC) and two serine/ threonine protein phosphatases, PP1 and PP2A. Importantly, the protein kinase A-anchoring protein, mAKAP, is found and its presence in the macromolecular complex suggests that these regulatory enzymes are coordinately positioned to regulate NCX1 as has been found in diverse cells for a number of channel proteins. Dual immunocytochemical staining showed the colocalization of NCX1 protein with mAKAP and PKA-RI proteins in cardiomyocytes. Finally, leucine/isoleucine zipper motifs have been identified as possible sites of interaction. Our finding of an NCX1 macromolecular complex in heart suggests how NCX1 regulation is achieved in heart and other cells. The existence of the NCX1 macromolecular complex may also provide an explanation for recent controversial findings.The Na ϩ /Ca 2ϩ exchanger, NCX1, is an integral membrane protein that is expressed in many tissues and is involved in cellular Ca 2ϩ homeostasis (1, 2). The expression level of NCX1 is modulated during development (3, 4) and under pathological conditions (5-9). The Na ϩ /Ca 2ϩ exchanger activity has been shown to be affected by the ions that it transports (Na ϩ and Ca 2ϩ ) (10 -13), by protons (14,15), by phosphatidylinositol 4,5-bisphosphate in the membrane (16), and by exogenous agents including intracellular application of an inhibitor peptide (XIP) (17). However, regulation of NCX1 by PKA 1 has remained controversial (18 -23).Early studies suggested that ATP-dependent regulation of NCX1 occurred in squid axons (24,25) and in cardiac sarcolemmal vesicles (26), but these studies did not distinguish between direct ATP binding and ATP-dependent phosphorylation. Several studies were designed to resolve this problem. Hilgemann and colleagues (11,12,27,28) investigated the question by measuring NCX1 currents in giant excised patches. The work used two preparations, NCX1-expressing Xenopus oocytes (27) or cardiac myocytes expressing native NCX1 (11,12,28). These investigations found no functional change in cardiac NCX1 activity following application of PKA or protein kinase C (PKC) catalytic subunits to...

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Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure.

Cited by 537 publications

References 46 publications

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

Excitation-contraction coupling and mitochondrial energetics

Sodium/Calcium Exchanger (NCX1) Macromolecular Complex

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