Regulation and Role of the Presynaptic and Myocardial Na<sup>+</sup>/H<sup>+</sup> Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

Leineweber, Kirsten; Heusch, Gerd; Schulz, Rainer

doi:10.1111/j.1527-3466.2007.00010.x

Cited by 33 publications

(16 citation statements)

References 41 publications

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“…*P Ͻ 0.05. perfusion with veratridine leads to a massive reduction of NET activity, with a small amount of release of [ 3 H]NE. This is in line with data that have shown that NET function is dependent from the intracellular Na ϩ gradient (38) and, at least during acute changes of intracellular pH and ATP as observed during, e.g., ischemia-reperfusion, from the presynaptic Na ϩ /H ϩ exchanger (38). However, the aim of the present study was to investigate the chronic effects of a HS diet over several weeks.…”

Section: Discussionsupporting

confidence: 47%

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Kreußer

Lehmann

Riffel

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Kreusser MM, Lehmann LH, Riffel JH, Haass M, Maser-Gluth C, Backs J, Katus HA, Buss SJ. Aldosterone augments Na ϩ -induced reduction of cardiac norepinephrine reuptake. Am J Physiol Heart Circ Physiol 307: H1169 -H1177, 2014. First published August 15, 2014; doi:10.1152/ajpheart.00193.2014.-Impairment of the cardiac norepinephrine (NE) reuptake by the neuronal NE transporter contributes to enhanced cardiac NE net release in congestive heart failure. Elevated plasma levels of aldosterone (AL) promote sympathetic overstimulation in failing hearts by unclear mechanisms. Our aim was to evaluate if elevated AL and/or alterations in Na ϩ intake regulate cardiac NE reuptake. To test the effects of AL and Na ϩ on cardiac NE reuptake, Wistar rats were fed a normal-salt (NS) diet (0.2% NaCl), a low-salt (LS) diet (0.015% NaCl), or a high-salt (HS) diet (8% NaCl). Another group of animals received AL infusion alone (0.75 g/h) or AL infusion plus HS diet. Specific cardiac [ 3 H]NE uptake via the NE transporter in a Langendorff preparation and AL plasma levels were measured at different time points between 5 and 42 days of treatment. To compare these findings from healthy animals with a disease model, Dahl salt-sensitive rats were investigated as a model of congestive heart failure with endogenously elevated AL. In summary, neither exogenous nor endogenous elevations of AL alone were sufficient to reduce cardiac NE reuptake. Only the HS diet induced a reduction of NE reuptake by 26%; additional infusion of AL augmented this effect to a further reduction of NE reuptake by 36%. In concordance, Dahl salt-sensitive rats treated with a HS diet displayed elevated AL and a marked reduction of NE reuptake. We conclude that exogenous or endogenous AL elevations alone do not reduce cardiac NE reuptake, but AL serves as an additional factor that negatively regulates cardiac NE reuptake in concert with HS intake. congestive heart failure; norepinephrine; aldosterone; sodium; Dahl rats ALDOSTERONE (AL), an endogenous mineralocorticoid receptor (MR) agonist, is known to regulate not only renal electrolyte and body fluid balance but also promotes cardiac and vascular fibrosis, baroreceptor dysfunction, parasympathetic inhibition, and sympathetic activation (56, 62). The renin-angiotensinaldosterone system (RAAS) is known to play a central role in the pathophysiology and progression of congestive heart failure (CHF) (7,35,45,46). Its activation is associated with a poor prognosis of CHF patients (49,57). Recent data have revealed that elevated levels of AL identify subjects in a normotensive population with an increased risk to develop hypertension (59), and circulating AL levels are positively correlated with left ventricular (LV) mass in patients with hypertension (53). Now, increased plasma AL is regarded as an important risk factor in CHF (36, 57). Since the Randomized Aldactone Evaluation Study (RALES) (46) revealed a reduced mortality of CHF patients treated with the MR antagonist spironolactone, it has remained unclear which action ...

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Section: Discussionsupporting

confidence: 47%

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Kreußer

Lehmann

Riffel

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…content [6]. The NHE1 activity contributes to cardiac hypertrophy [61,65,66,100]. Accordingly, cardiac hypertrophy and its progression to heart failure can be strongly reduced by NHE1 inhibitors [1,24,60].…”

Section: Discussionmentioning

confidence: 98%

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

et al. 2012

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Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual development of cardiac failure. Compelling evidence points to a critical role of enhanced cardiac Na(+)/H(+) exchanger (NHE1) activity in the underlying pathophysiology. The signaling triggering up-regulation of NHE1 remained, however, ill defined. The present study explored the involvement of the serum- and glucocorticoid-inducible kinase Sgk1 in cardiac remodeling due to transverse aortic constriction (TAC). To this end, experiments were performed in gene targeted mice lacking functional Sgk1 (sgk1 (-/-)) and their wild-type controls (sgk1 (+/+)). Transcript levels have been determined by RT-PCR, cytosolic pH (pH( i )) utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, Na(+)/H(+) exchanger activity by the Na(+)-dependent realkalinization after an ammonium pulse, ejection fraction (%) utilizing cardiac cine magnetic resonance imaging and cardiac glucose uptake by PET imaging. As a result, TAC increased the mRNA expression of Sgk1 in sgk1 (+/+) mice, paralleled by an increase in Nhe1 transcript levels as well as Na(+)/H(+) exchanger activity, all effects virtually abrogated in sgk1 (-/-) mice. In sgk1 (+/+) mice, TAC induced a decrease in Pgc1a mRNA expression, while Spp1 mRNA expression was increased, both effects diminished in the sgk1 (-/-) mice. TAC was followed by a significant increase of heart and lung weight in sgk1 (+/+) mice, an effect significantly blunted in sgk1 (-/-) mice. TAC increased the transcript levels of Anp and Bnp, effects again significantly blunted in sgk1 (-/-) mice. TAC increased transcript levels of Collagen I and III as well as Ctgf mRNA and CTGF protein abundance, effects significantly blunted in sgk1 (-/-) mice. TAC further decreased the ejection fraction in sgk1 (+/+) mice, an effect again attenuated in sgk1 (-/-) mice. Also, cardiac FDG-glucose uptake was increased to a larger extent in sgk1 (+/+) mice than in sgk1 (-/-) mice after TAC. These observations point to an important role for SGK1 in cardiac remodeling and development of heart failure following an excessive work load.

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“…The cardiac Nhe1 has emerged as a key factor in myocardial remodeling [65,66,67]. Enhanced Nhe1 activity contributes to the pathophysiology of myocardial reperfusion injury [68], cardiac insufficiency [69] and cardiac hypertrophy [42,43,70,71,72]. Accordingly, upregulation of Nhe1 may trigger [73] and pharmacological inhibition of Nhe1 counteracts [65,66,67] cardiac hypertrophy and progression to heart failure.…”

Section: Discussionmentioning

confidence: 99%

Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone

Voelkl

Pasham

Ahmed

et al. 2013

Cell Physiol Biochem

683

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Background/Aims: The serum- and glucocorticoid-inducible kinase Sgk1 contributes to cardiac remodeling and development of heart failure, which is paralelled by Sgk1-dependent stimulation of the cardiac Na⁺/H⁺ exchanger Nhe1. Glucocorticoids are powerful stimulators of Sgk1 expression and influence cardiac remodeling. The present study thus explored whether the glucocorticoid receptor agonist dexamethasone influenced cardiac Sgk1 expression, as well as activity, expression and phosphorylation at Ser⁷⁰³ of the cardiac Na⁺/H⁺ exchanger Nhe1. Methods: Experiments were performed in HL-1 cardiomyocytes and gene targeted mice lacking functional Sgk1 (sgk1^-/-) and respective wild type mice (sgk1^+/+). Gene expression was determined by quantitative RT-PCR and Nhe1 phosphorylation was determined utilizing a specific antibody against a 14-3-3 binding motif at P-Ser⁷⁰³, which represents a putative phosphorylation site recognition motif for Sgk1 and is involved in Nhe1 activation. Cytosolic pH (pH_i) was determined utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence and Nhe activity by the Na⁺-dependent realkalinization after an ammonium pulse. Results: Treatment of HL-1 cardiomyocytes with dexamethasone was followed by a significant increase in Sgk1 mRNA expression, parallelled by increased Na⁺/H⁺ exchanger activity. Furthermore, dexamethasone significantly increased Nhe1 and Spp1 mRNA expression. The effects of dexamethasone were blunted by cotreatment of HL-1 cardiomyocytes with the Sgk1 inhibitor EMD638683. Cotreatment with Nhe1 inhibitor cariporide similarly prevented dexamethasone-stimulated Spp1 mRNA expression. In sgk1^+/+ mice, dexamethasone significantly increased cardiac Sgk1 mRNA levels. In sgk1^+/+ mice, but not in sgk1^-/- mice, dexamethasone significantly increased cardiac Nhe1 mRNA expression and Nhe1 phosphorylation at Ser⁷⁰³. Furthermore, cardiac Spp1, Ctgf, Nppa and Nppb mRNA levels were significantly increased in dexamethasone treated sgk1^+/+ mice, effects significantly blunted in sgk1^-/- mice. Conclusions: Sgk1 is critically involved in the phosphorylation and activation of the cardiac Na⁺/H⁺ exchanger Nhe1.

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Regulation and Role of the Presynaptic and Myocardial Na⁺/H⁺ Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

Cited by 33 publications

References 41 publications

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone

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Regulation and Role of the Presynaptic and Myocardial Na+/H+ Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

Cited by 33 publications

References 41 publications

Aldosterone augments Na+-induced reduction of cardiac norepinephrine reuptake

Aldosterone augments Na+-induced reduction of cardiac norepinephrine reuptake

Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

Sgk1-Dependent Stimulation of Cardiac Na+/H+Exchanger Nhe1 by Dexamethasone

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Product

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About

Regulation and Role of the Presynaptic and Myocardial Na⁺/H⁺ Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Aldosterone augments Na⁺-induced reduction of cardiac norepinephrine reuptake

Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone