Inhibiting p90 Ribosomal S6 Kinase Prevents Na
            <sup>+</sup>
            -H
            <sup>+</sup>
            Exchanger–Mediated Cardiac Ischemia-Reperfusion Injury

Maekawa, Naoya; Abe, Jun; Shishido, Tetsuro; Itoh, Seigo; Ding, Bo; Sharma, Virendra K.; Sheu, Shey Shing; Blaxall, Burns C.; Berk, Bradford C.

doi:10.1161/circulationaha.105.563486

Cited by 75 publications

(84 citation statements)

References 32 publications

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“…U0126 had similar neuroprotection as inhibition of NHE1 activity by HOE 642 or genetic ablation. It has been reported that inhibition of p90 RSK by transgenic expression of a p90 RSK mutant enhances the tolerance of mouse myocardium to ischemia and reperfusion-induced injury, probably through reduced sarcolemmal NHE1 activation (29). This is consistent with our result that activation of the ERKp90 RSK pathway is detrimental and responsible for the activation of NHE1 in ischemic neurons.…”

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftersupporting

confidence: 93%

“…A serine/threonine kinase p90 RSK , a downstream substrate of ERK1/2, has been reported to directly phosphorylate NHE1 at Ser 703 in the regulatory C-terminal domain and activate the exchanger activity in response to growth factors (23). Phosphorylation of Ser 703 on NHE1 by p90 RSK creates a binding motif for protein 14-3-3 ␤ (17) and stabilizes NHE1 in an active state in ischemic cardiomyocytes (29).…”

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

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ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

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The function and regulation of Na ؉ /H ؉ exchanger isoform 1 (NHE1) following cerebral ischemia are not well understood. In this study, we demonstrate that extracellular signal-related kinases (ERK1/2) play a role in stimulation of neuronal NHE1 following in vitro ischemia. NHE1 activity was significantly increased during 10 -60 min reoxygenation (REOX) after 2-h oxygen and glucose deprivation (OGD). OGD/REOX not only increased the V max for NHE1 but also shifted the K m toward decreased [H ؉ ] i . These changes in NHE1 kinetics were absent when MAPK/ERK kinase (MEK) was inhibited by the MEK inhibitor U0126. There were no changes in the levels of phosphorylated ERK1/2 (p-ERK1/2) after 2 h OGD. The p-ERK1/2 level was significantly increased during 10 -60 min REOX, which was accompanied by nuclear translocation. U0126 abolished REOX-induced elevation and translocation of p-ERK1/2. We further examined the ERK/90-kDa ribosomal S6 kinase (p90 RSK ) signaling pathways. At 10 min REOX, phosphorylated NHE1 was increased with a concurrent elevation of phosphorylation of p90 RSK , a known NHE1 kinase. Inhibition of MEK activity with U0126 abolished phosphorylation of both NHE1 and p90 RSK . Moreover, neuroprotection was observed with U0126 or genetic ablation or pharmacological inhibition of NHE1 following OGD/REOX. Taken together, these results suggest that activation of ERK1/2-p90 RSK pathways following in vitro ischemia phosphorylates NHE1 and increases its activity, which subsequently contributes to neuronal damage. The Naϩ /H ϩ exchanger (NHE) 2 family is a group of membrane transport proteins that catalyzes the secondary active electroneurtral exchange of one Na ϩ for one H ϩ . To date, nine NHE isoforms (NHE1-9) have been cloned in mammalian tissues (1). Na ϩ /H ϩ exchanger isoform 1 (NHE1) is the most abundant NHE isoform in the rat central nervous system (2) and crucial in regulation of neuronal pH i (3, 4). We have recently reported that NHE1 activity plays an important role in neuronal damage in both in vitro and in vivo ischemic models (4). Inhibition of NHE1 activity during OGD/REOX prevents intracellular Na ϩ and Ca 2ϩ overload and thus reduces the Ca 2ϩ -mediated cascade of deleterious events (4). In acutely isolated CA1 neurons, an anoxia-triggered intracellular alkalization depends on activation of NHE1 (5). We also found that NHE1 activity is stimulated in cortical astrocytes following in vitro ischemia (6). However, whether NHE1 activity is overstimulated in cortical neurons following in vitro ischemia remains unknown.NHE1 has two large functional domains. The N-terminal transmembrane domain (ϳ500 amino acids) is responsible for cation translocation, and the cytoplasmic C-terminal domain (ϳ315 amino acids) is the main regulatory site for the NHE1 activity (7). The distal C-terminal tail of NHE1 contains a number of serine and threonine residues that are phosphorylated by several protein kinases, including extracellular signal-related kinases (ERK1/2) and 90-kDa ribosomal S6 kinase (p90 RSK ) (8). Activa...

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Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftersupporting

confidence: 93%

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

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“…9 A recent publication suggested that inhibition of the exchanger only after its activation by acidosis, but not during its basal function, may present therapeutic advantages. 11 Although inhibition of the NHE-1 only after critical situations and not under basal conditions seems unrealistic, it was reported that inhibition of p90 ribosomal S6 kinase, which phosphorylates the cytosolic tail of the NHE-1, decreased agonistic activated NHE-1 function without inhibiting its basal homeostatic function. 11 More interestingly, this inhibition was accompanied by beneficial effects.…”

Section: T He Namentioning

confidence: 99%

Phosphodiesterase 5A Inhibition Induces Na ⁺ /H ⁺ Exchanger Blockade and Protection Against Myocardial Infarction

et al. 2007

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Abstract-Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na ϩ /H ϩ exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg Ϫ1 day Ϫ1 ) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.

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“…39 Several protein kinases have been shown to be involved in the phosphorylation of NHE1, including PKC, 40,41 ROCK, 42,43 MAPK-dependent pathways, [44][45][46] and p90 rsk . 45,47 The impact of phosphorylation on activity varies, in some cases increasing exchange activity or shifting the pH-dependent activation of NHE1 to more alkaline pH i . 105 In contrast, phosphorylation of the high-affinity calmodulin binding site at Ser-648 by protein kinase B/Akt prevents the NHE1-calmodulin interaction and thus inhibits NHE1 ion transport activity.…”

Section: Mechanisms Controlling Nhe1 Activity and Expression In Pasmcmentioning

confidence: 99%

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Huetsch

Shimoda

2015

Pulm. circ.

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Intracellular pH (pH i ) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium-hydrogen exchange (NHE) is an important contributor to pH i control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension.

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Inhibiting p90 Ribosomal S6 Kinase Prevents Na ⁺ -H ⁺ Exchanger–Mediated Cardiac Ischemia-Reperfusion Injury

Cited by 75 publications

References 32 publications

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Phosphodiesterase 5A Inhibition Induces Na ⁺ /H ⁺ Exchanger Blockade and Protection Against Myocardial Infarction

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

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Inhibiting p90 Ribosomal S6 Kinase Prevents Na + -H + Exchanger–Mediated Cardiac Ischemia-Reperfusion Injury

Cited by 75 publications

References 32 publications

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Phosphodiesterase 5A Inhibition Induces Na + /H + Exchanger Blockade and Protection Against Myocardial Infarction

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

Contact Info

Product

Resources

About

Inhibiting p90 Ribosomal S6 Kinase Prevents Na ⁺ -H ⁺ Exchanger–Mediated Cardiac Ischemia-Reperfusion Injury

Phosphodiesterase 5A Inhibition Induces Na ⁺ /H ⁺ Exchanger Blockade and Protection Against Myocardial Infarction

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension