Hydroperoxide-induced oxidative stress alters pyridine nucleotide metabolism in neonatal heart muscle cells

Janero, David R.; Hreniuk, David; Sharif, H.; Prout, Kelly C.

doi:10.1152/ajpcell.1993.264.6.c1401

Cited by 35 publications

(15 citation statements)

References 24 publications

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“…These findings can be explained by the activity of adenylate kinase, an impaired recharge of the adenylic system and an enhanced leakage from membranes, permeabilized by the lack of ATP. In any case, our results on adenine nucleotides agree with those reported by other authors [24] and suggest a development of a marked energy depletion due to PARP activation.…”

Section: Discussionsupporting

confidence: 93%

Poly(ADP-ribose) Polymerase Activation and Cell Injury in the Course of Rat Heart Heterotopic Transplantation

Fiorillo

Pace

Ponziani

et al. 2002

Free Radical Research

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Free radicals and other reactive species generated during reperfusion of ischemic tissues may cause DNA damage and, consequently, the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). An excessive PARP activation may result in a depletion of intracellular NAD + and ATP, hence cell suffering and, ultimately, cell death. The present study is aimed at clarifying the role of PARP in a heart transplantation procedure and the contribution of myocyte necrosis and/or apoptosis to this process.In our experimental model, rat heart subjected to heterotopic transplantation, low temperature global ischemia (2 h) was followed by an in vivo reperfusion (30 or 60 min). Under these conditions clear signs of oxidative stress, such as lipoperoxidation and DNA strand breaks, were evident. In addition to a marked activation, accompanied by a significant NAD + and ATP depletion, PARP protein levels significantly increased after 60 min of reperfusion. Ultrastructural analysis showed nuclear clearings, intracellular oedema and plasma membrane discontinuity. Other relevant observations were the absence of typical signs of apoptosis like caspase-3 activation and PARP cleavage, random DNA fragmentation, rise in serum levels of heart damage markers. Our results suggest that during heart transplantation, the activation of PARP, causing energy depletion, results in myocardial cell injury whose dominant feature, at least in our experimental model, is necrosis rather than apoptosis.

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Section: Discussionsupporting

confidence: 93%

Poly(ADP-ribose) Polymerase Activation and Cell Injury in the Course of Rat Heart Heterotopic Transplantation

Fiorillo

Pace

Ponziani

et al. 2002

Free Radical Research

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“…After incubation with 500 M H 2 O 2 for 5 min, the rotenone-induced NAD(P)H signal decreased to 34 Ϯ 0.4% as compared with control, but the effect of H 2 O 2 at 15 M was already significant (83 Ϯ 3.6%). The effect of H 2 O 2 on the NAD(P)H level in glucose-free medium H 2 O 2 has been reported to inhibit gliceraldehyde-3-phosphatedehydrogenase (Hyslop et al, 1988;Janero et al, 1993); thus we investigated whether a reduced NADH production in the glycolysis could contribute to the results shown in Figures 3 and 4. For this, the effect of H 2 O 2 on ⌬NAD(P)H was investigated in the absence of glucose, using the experimental protocol shown in Figure 3 (inset).…”

Section: Changes In the Nad(p)h Fluorescence Caused By To H 2 Omentioning

confidence: 94%

Inhibition of Krebs Cycle Enzymes by Hydrogen Peroxide: A Key Role of α-Ketoglutarate Dehydrogenase in Limiting NADH Production under Oxidative Stress

2000

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In this study we addressed the function of the Krebs cycle to determine which enzyme(s) limits the availability of reduced nicotinamide adenine dinucleotide (NADH) for the respiratory chain under H 2 O 2 -induced oxidative stress, in intact isolated nerve terminals. The enzyme that was most vulnerable to inhibition by H 2 O 2 proved to be aconitase, being completely blocked at 50 M H 2 O 2 . ␣-Ketoglutarate dehydrogenase (␣-KGDH) was also inhibited but only at higher H 2 O 2 concentrations (Ն100 M), and only partial inactivation was achieved. The rotenone-induced increase in reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] fluorescence reflecting the amount of NADH available for the respiratory chain was also diminished by H 2 O 2 , and the effect exerted at small concentrations (Յ50 M) of the oxidant was completely prevented by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNUinsensitive decline by H 2 O 2 in the rotenone-induced NAD(P)H fluorescence correlated with inhibition of ␣-ketoglutarate dehydrogenase. Decrease in the glutamate content of nerve terminals was induced by H 2 O 2 at concentrations inhibiting aconitase. It is concluded that (1) aconitase is the most sensitive enzyme in the Krebs cycle to inhibition by H 2 O 2 , (2) at small H 2 O 2 concentrations (Յ50 M) when aconitase is inactivated, glutamate fuels the Krebs cycle and NADH generation is unaltered, (3) at higher H 2 O 2 concentrations (Ն100 M) inhibition of ␣-ketoglutarate dehydrogenase limits the amount of NADH available for the respiratory chain, and (4) increased consumption of NADPH makes a contribution to the H 2 O 2 -induced decrease in the amount of reduced pyridine nucleotides. These results emphasize the importance of ␣-KGDH in impaired mitochondrial function under oxidative stress, with implications for neurodegenerative diseases and cell damage induced by ischemia/reperfusion.

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“…The second possibility is not unreasonable considering a previous report showing that oxidative stress activates protein ADP-ribosylation in the catabolism of one major route of pyridine nucleotide (54). If this is the case, ADP-ribosylation activated by CH could be responsible for the decline of the elongation step, as this reaction is a nonreversible phenomenon.…”

Section: Effect Of Oxidative Stress On Elongation Factor-2mentioning

confidence: 95%

Effect of Oxidative Stress, Produced by Cumene Hydroperoxide, on the Various Steps of Protein Synthesis

Ayala

Parrado

Bougria

et al. 1996

Journal of Biological Chemistry

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We have studied the effect of oxidative stress on protein synthesis in rat liver. Cumene hydroperoxide (CH) was used as an oxidant agent. The approach used was to determine the ribosomal state of aggregation and the time for assembly and release of polypeptide chains in the process of protein synthesis in rat liver in vivo. The results suggest that the elongation step is the most sensitive to CH treatment. The measurement of both carbonyl groups content and ADP-ribosylatable elongation factor 2 (EF-2), the main protein involved in the elongation step, indicates that under CH treatment EF-2 is oxidatively modified and a lower amount of active EF-2 is present. These results are corroborated by in vitro oxidation of EF-2 and could explain for the decline in the elongation step.The effect of oxidative stress on protein metabolism have been reported by various laboratories (1-13). Most of these studies have focused on protein degradation, the major finding being that oxidatively modified proteins become susceptible to proteolytic digestion (2, 4 -7, 9 -13). With respect to protein synthesis, the effect of active oxygen species has been less studied and has been addressed by using oxidizing agents (14 -16). One of such compounds is cumene hydroperoxide (CH), 1 which has been used as an intracellular source of reactive oxygen intermediates (17)(18)(19)(20)(21)(22). Besides its damaging effects such as membrane damage, cell lysis, organ necrosis, tumor promotion (20), and certain aspects of aging (23), it has been reported that this compound and/or cytotoxic aldehydes derived from it inhibit protein synthesis in human skin fibroblasts (14). These in vitro results were obtained by measuring the incorporation of radioactive amino acid precursors into proteins, a methodology which is not suitable when using whole animal systems because of the difficulty in measuring the specific activity of the amino acid precursor pool (23). Furthermore, a detailed molecular mechanism of the decline of protein synthesis caused by the oxidant is not available.Because of the potential importance of decreased protein synthesis in structural and functional deterioration of the cell, the molecular basis for decreased rate of protein synthesis by CH, and hence by oxidative stress, is of interest, especially since this decrease may be an important contributor to certain processes in which free radicals seem to be involved, such as aging (25).In order to understand the mechanism underlying the inhibition of protein synthesis by CH, we have studied: 1) which of the individual steps in polypeptide synthesis is most affected, and 2) the possible mechanism of how active oxygen species may interact with the protein synthetic machinery.The effect of CH on the stages of protein synthesis has been studied by investigating the ribosome half-transit time (elongation time) required for the synthesis of an average halflength of a nascent polypeptide chain (26), and the ribosomal state of aggregation (27, 28), which is reflected by the polyribosomal profiles....

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Hydroperoxide-induced oxidative stress alters pyridine nucleotide metabolism in neonatal heart muscle cells

Cited by 35 publications

References 24 publications

Poly(ADP-ribose) Polymerase Activation and Cell Injury in the Course of Rat Heart Heterotopic Transplantation

Poly(ADP-ribose) Polymerase Activation and Cell Injury in the Course of Rat Heart Heterotopic Transplantation

Inhibition of Krebs Cycle Enzymes by Hydrogen Peroxide: A Key Role of α-Ketoglutarate Dehydrogenase in Limiting NADH Production under Oxidative Stress

Effect of Oxidative Stress, Produced by Cumene Hydroperoxide, on the Various Steps of Protein Synthesis

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