Na+/Ca2+ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models

Castaldo, Pasqualina; Macrì, Maria Loredana; Lariccia, Vincenzo; Matteucci, Alessandra; Maiolino, Marta; Gratteri, Santo; Amoroso, Salvatore; Magi, Simona

doi:10.1016/j.ejphar.2016.11.045

Cited by 19 publications

(29 citation statements)

References 69 publications

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“…2a,b and Supplementary Fig. 1), as previously reported 19 , glutamate supplementation during the reoxygenation phase fully prevented H/R damage only in H9c2-NCX1 but not in H9c2-WT cells (Fig. 2a,b).…”

Section: Resultssupporting

confidence: 88%

“…2a,c). SN-6 per se has no effect on H9c2-NCX1 cell viability under normoxia 19 or when introduced only at the reperfusion during our H/R protocol (Figs 1 and 2a,c). Noteworthy, the same results were obtained in primary culture of rat adult cardiomyocytes, which endogenously express NCX1.…”

Section: Resultsmentioning

confidence: 83%

“…Noteworthy, the same results were obtained in primary culture of rat adult cardiomyocytes, which endogenously express NCX1. When cardiomyocytes were subjected to the H/R protocol 19 shown in Fig. 1b, we found that 1 mM glutamate greatly reduced H/R-induced cell damage, and that glutamate-induced protection was lost in the presence of SN-6 (Fig.…”

Section: Resultsmentioning

confidence: 85%

“…When cells were subjected to 3 h of hypoxia followed by 5 h of reoxygenation (Fig. 1a), we found that cell damage, as assessed by extracellular LDH levels 19 and fluorescein diacetate/propidium iodide (FDA/PI) double staining 21,22 , was significantly higher in both H9c2 cell lines than their respective normoxic controls (Fig. 2a,b and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 96%

“…We initially established an in vitro model of H/R based on two H9c2 clones 19 , H9c2-WT (not expressing endogenous NCX1 under our culture conditions 17,20 and H9c2-NCX1 (generated from H9c2-WT and stably expressing canine NCX1 17 ). When cells were subjected to 3 h of hypoxia followed by 5 h of reoxygenation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Maiolino

Castaldo

Lariccia

et al. 2017

Sci Rep

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Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial energy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here we investigated the role of NCX1 in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

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Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Maiolino

Castaldo

Lariccia

et al. 2017

Sci Rep

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Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger

Magi

Castaldo

Lariccia

et al. 2020

The First Outstanding 50 Years of “Università Politecnica Delle Marche”

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of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease

Magi

Piccirillo

Amoroso

2019

Cell. Mol. Life Sci.

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Glutamate is the major excitatory neurotransmitter in the central nervous system. Beyond this function, glutamate also plays a key role in intermediary metabolism in all organs and tissues, linking carbohydrate and amino acid metabolism via the tricarboxylic acid cycle. Under both physiological and pathological conditions, we have recently found that the ability of glutamate to fuel cell metabolism selectively relies on the activity of two main transporters: the sodium-calcium exchanger (NCX) and the sodium-dependent excitatory amino-acid transporters (EAATs). In ischemic settings, when glutamate is administered at the onset of the reoxygenation phase, the coordinate activity of EAAT and NCX allows glutamate to improve cell viability by stimulating ATP production. So far, this phenomenon has been observed in both cardiac and neuronal models. In this review, we focus on the most recent findings exploring the unusual activity of glutamate as a potential survival factor in different settings. KeywordsAmino-acid transporters • ATP • Cell viability • Ischemia/reperfusion • Sodium-calcium exchanger Abbreviations AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AGCs Aspartate/glutamate carriers AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid DL-TBOA DL-Threo-β-benzyloxyaspartic acid EAAC1 Excitatory amino acid carrier 1 EAATs Excitatory amino-acid transporters KA Kainate GLAST Glutamate-aspartate transporter GLT1 Glutamate transporter 1 mGluR Metabotropic glutamate receptors NCX Sodium-calcium exchanger NMDA N-Methyl-d-aspartate SN-6 2-[[4-[(4-Nitrophenyl)methoxy]phenyl] methyl]-4-thiazolidinecarboxylic acid ethyl ester Glutamate as neurotransmitterThe role of the glutamatergic neurotransmission into the human central nervous system (CNS) has been consolidated through a long research history over more than 70 years [1].The presence of high concentrations of glutamate in the brain was first identified in the 1930s, but at that time it was mainly considered an energy source for the CNS [2], as it has been ubiquitously found, with special regard to cytosolic and mitochondrial compartments. Only in 1984 was glutamate fully recognized as the major excitatory neurotransmitter in the mammalian brain [3] and now its functions within the CNS are well established. Glutamate is involved in many aspects of normal brain function, including cognition, memory and learning, cell migration, differentiation and death during the development of the CNS [4]. Furthermore, glutamate seems to have a role also in the peripheral nervous system and in endocrine cells as well [4,5]. Despite its ubiquitous nature, glutamate concentrations are maintained at homeostatic levels through the tightly Cellular and Molecular Life Sciences * Simona Magi

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Na+/Ca2+ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models

Cited by 19 publications

References 69 publications

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger

The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease

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