Glycine protects cardiomyocytes against lethal reoxygenation injury by inhibiting mitochondrial permeability transition

Ruiz‐Meana, Marisol; Pina, Pilar; Garcı́a-Dorado, David; Rodríguez‐Sinovas, Antonio; Barba, Ignasi; Miró-Casas, Elisabet; Mirabet, Maribel; Soler‐Soler, Jordi

doi:10.1113/jphysiol.2004.068320

Cited by 70 publications

(64 citation statements)

References 32 publications

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“…In relation to this, it is worth mentioning here the recently described increase in apparent detection of Gly by HRMAS with increased recording time in GBM biopsies (48), which was also interpreted by the authors as suggesting higher gly visibility in GBM ex vivo with respect to the in the in vivo tumour MRS pattern. The concentration of gly that displays a protective effect in the various cell systems mentioned above is in the 3-5 mM range (51)(52)(53). This value is very close to the gly content found by us in GBM (3.28 µmol/gtw, Table V).…”

Section: Comparison Of Mi/gly Calculated From In Vivo Data and Mi/glysupporting

confidence: 71%

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo mrs

Candiota

Majós

Julià‐Sapé

2011

Journal of the Belgian Society of Radiology

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MRI and MRS are established methodologies for evaluating intracranial lesions. One MR spectral feature suggested for in vivo grading of astrocytic tumours is the apparent myo-Inositol (mI) intensity (ca 3.55ppm) at short echo times, although glycine (gly) may also contribute in vivo to this resonance. The purpose of this study was to quantitatively evaluate the mI + gly contribution to the recorded spectral pattern in vivo and correlate it with in vitro data obtained from perchloric acid extraction of tumour biopsies. Patient spectra (n = 95) at 1.5T at short (20-31 ms) and long (135-136 ms) echo times were obtained from the INTERPRET MRS database (http://gabrmn.uab.es/interpretvalidateddb/). Phantom spectra were acquired with a comparable protocol. Spectra were automatically processed and the ratios of the (mI + gly) to Cr peak heights ((mI + gly)/Cr) calculated. Perchloric acid extracts of brain tumour biopsies were analysed by high-resolution NMR at 9.4T. The ratio (mI + gly)/Cr decreased significantly with astrocytic grade in vivo between low-grade astrocytoma (A2) and glioblastoma multiforme (GBM). In vitro results displayed a somewhat different tendency, with anaplastic astrocytomas having significantly higher (mI + gly)/Cr than A2 and GBM. The discrepancy between in vivo and in vitro data suggests that the NMR visibility of glycine in glial brain tumours is restricted in vivo.

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Section: Comparison Of Mi/gly Calculated From In Vivo Data and Mi/glysupporting

confidence: 71%

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo mrs

Candiota

Majós

Julià‐Sapé

2011

Journal of the Belgian Society of Radiology

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“…However, in marked contrast to the findings in whole perfused hearts, neither apoptotic nor necrotic cell death of HL-1 cells under these conditions was attenuated by 15 min acidic reperfusion. This is in apparent contradiction to one earlier study in HL-1 cells, in which a brief acidic treatment was found to exert significant protection against I/R damage [45]. Notably, however, where we employed true hypoxia in combination with physiologically relevant CO 2 /HCO 3 -buffering, this study [45] employed a "simulated ischemia" protocol in which glucose-and mitochondrial metabolism is poisoned by cyanide and 2-deoxyglucose (2-DOG) to completely block both.…”

Section: Discussioncontrasting

confidence: 53%

“…The HL-1 cells were exposed to 5 h of simulated ischemia (0.5% O 2 , 5% CO 2 , HCO 3 -buffering to pH 6.0, increased K + , and no glucose), followed by 120 min reperfusion, of which the first 15 min was either at pH 7.4 or pH 6.0, and in the absence or presence of EIPA. HL-1 cells undergoing ischemia followed by 120 min neutral reperfusion exhibited a marked increase in both necrotic and apoptotic cell death compared to normoxic controls, consistent with previous reports by us and others [3,18,45]. However, in marked contrast to the findings in whole perfused hearts, neither apoptotic nor necrotic cell death of HL-1 cells under these conditions was attenuated by 15 min acidic reperfusion.…”

Section: Discussioncontrasting

confidence: 51%

The Cardioprotective Effect of Brief Acidic Reperfusion after Ischemia in Perfused Rat Hearts is not Mimicked by Inhibition of the Na<sup>+</sup>/H<sup>+</sup> Exchanger NHE1

Andersen

Bentzen²,

Salling³

et al. 2011

Cell Physiol Biochem

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Background: Ischemic postconditioning (PostC), i.e. brief ischemia-reperfusion cycles before full reperfusion, is protective against cardiac ischemia/reperfusion (I/R) injury. Inhibition of the Na⁺/H⁺ exchanger NHE1 and delayed intracellular pH-normalization have been proposed to underlie protection by PostC. Methods and Results: We used Langendorff perfused rat hearts exposed to 35 min global ischemia to show that 15 min acidic (pH 6.5) treatment at onset of reperfusion decreased infarct size and functional deterioration at least to the same extent as PostC. In contrast, NHE1 inhibition by EIPA was detrimental. To evaluate HL-1 atrial cardiomyocytes as a cellular model for PostC, we exposed the cells to simulated ischemia/reperfusion (I/R) mimicking that in perfused hearts. Necrosis and apoptosis induced by I/R were unaffected by 15 min of pH 6.0 at onset of reperfusion. I/R increased the activity of c-Jun N-terminal Kinase 1/2 (JNK1/2) and Akt, but not of p38 MAPK, with no further effect of acidic reperfusion or EIPA. Conclusion: In rat hearts, 15 min acidic reperfusion improves myocardial performance at least as much as does PostC, whereas NHE1 inhibition is detrimental. In contrast, in HL-1 cardiomyocytes, acidic reperfusion or NHE1 inhibition affect neither survival nor JNK1/2-, Akt-, and p38 MAPK activity after I/R, pointing to different mechanisms of damage and protection in these systems.

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“…The results demonstrated that GLY receptor α 1 and β subunitimmunoreactive spots were found not only on the membrane but also in the cytoplasm of cardiomyocytes; this finding is different from that in neurons. Recently, Ruiz-Meana et al found that intracellular glycine exerted an inhibitory effect on mitochondrial permeability transition in cardiomyocytes and that intracellular glycine depletion made the cells more vulnerable to necrotic death during myocardial hypoxia/ reoxygenation [24] . These findings suggest that GLY can act directly on the mitochondria of cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

Wang

et al. 2009

Acta Pharmacol Sin

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Aim: Previous studies have demonstrated that glycine (GLY) markedly reduces lipopolysaccharide (LPS)-induced myocardial injury. However, the mechanism of this effect is still unclear. The present study investigated the effect of GLY on cytosolic calcium concentration ([Ca 2+ ] c ) and tumor necrosis factor-α (TNFα) production in cardiomyocytes exposed to LPS, as well as whether the glycine-gated chloride channel is involved in this process. Methods: Neonatal rat cardiomyocytes were isolated, and the [Ca 2+ ] c and TNFα levels were determined by using Fura-2 and a Quantikine enzyme-linked immunosorbent assay, respectively. The distribution of the GLY receptor and GLY-induced currents in cardiomyocytes were also investigated using immunocytochemistry and the whole-cell patch-clamp technique, respectively. Results: LPS at concentrations ranging from 10 ng/mL to 100 µg/mL significantly stimulated TNFα production. GLY did not inhibit TNFα production induced by LPS at concentrations below 10 ng/mL but did significantly decrease TNFα release stimulated by 100 µg/mL LPS and prevented an LPS-induced increase in [Ca 2+ ] c , which was reversed by strychnine, a glycine receptor antagonist. GLY did not block the isoproterenol-induced increase in [Ca 2+ ] c , but did prevent the potassium chloride-induced increase in [Ca 2+ ] c in cardiomyocytes. Strychnine reversed the inhibition of the KCl-stimulated elevation in [Ca 2+ ] c by GLY. In chloride-free buffer, GLY had no effect on the dipotassium hydrogen phosphate-induced increase in [Ca 2+ ] c . Furthermore, GLY receptor α 1 and β subunit-immunoreactive spots were observed in cardiomyocytes, and GLY-evoked currents were blocked by strychnine. Conclusion: Cardiomyocytes possess the glycine-gated chloride channel, through which GLY prevents the increase in [Ca 2+ ] c and inhibits the TNFα production induced by LPS at high doses in neonatal rat cardiomyocytes.

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Glycine protects cardiomyocytes against lethal reoxygenation injury by inhibiting mitochondrial permeability transition

Cited by 70 publications

References 32 publications

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo mrs

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo mrs

The Cardioprotective Effect of Brief Acidic Reperfusion after Ischemia in Perfused Rat Hearts is not Mimicked by Inhibition of the Na<sup>+</sup>/H<sup>+</sup> Exchanger NHE1

Glycine inhibits the LPS-induced increase in cytosolic Ca2+ concentration and TNFα production in cardiomyocytes by activating a glycine receptor

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