Nitric Oxide Toxicity in Islet Cells Involves Poly(ADP-Ribose) Polymerase Activation and Concomitant NAD+ Depletion

Radons, Jürgen; Heller, Birgit; Bürkle, Alexander; Hartmann, Bettina; Rodriguez, Maria-L.; Kröncke, Klaus‐Dietrich; Burkart, Volker; Kolb, Hubert

doi:10.1006/bbrc.1994.1368

Cited by 182 publications

(81 citation statements)

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“…Since DNA strand breaks were observed previously by us as crucial early events in the destruction of islet cells by NO [17], we determined whether ~-tocopherol would prevent DNA damage. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Suppression of nitric oxide toxicity in islet cells by α‐tocopherol

et al. 1995

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We show here that preincubation of pancreatic islet cells with a-toeopherol significantly improves their resistance to toxic doses of nitric oxide (NO). No protection was afforded by other antioxidants such as vitamin C or glutathione-monoethyl ester. The pathway of NO induced islet cell death involves DNA damage and excessive activation of poly(ADP-ribose)polymerase leading to irreversible depletion of intraeellular NAD +. a-Tocopherol was found to interfere at early steps of this pathway, by preventing the occurrence of DNA strand breaks. This indicates that a-tocopherol directly interacts with NO or its reactive intermediates. We conclude that a-tncopherol is not only part of the cellular defence system against oxygen radicals but also protects eukaryotie cells from NO toxicity.

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Section: Resultsmentioning

confidence: 99%

Suppression of nitric oxide toxicity in islet cells by α‐tocopherol

et al. 1995

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“…Excessive activation of poly(ADP-ribose) polymerase has been implicated to mediate cell death in different models of ischemia-reperfusion injury 10,40,42 as well as streptozotocininduced diabetes, 32 glutamate-induced neurotoxicity 5,49 and Alzheimer's disease. 27 The common feature in the pathogen- Figure 3 Poly(ADP-ribose) polymer immunohistochemistry on retinal sections to monitor PARP activation after ON transection with or without 3-ABA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…26 However, it has also been demonstrated that excessive PARP activation by various triggers resulting in depletion of NAD + and subsequent cellular ATP depletion ultimately leads to a necrotic-type cell death. 5,32,41,49 There is accumulating evidence that excessive PARP activation plays a key role in mediating ischemia-reperfusion-induced cerebral injury 10,11,38,42 and that infarct volume can be dramatically reduced by PARP inhibition and in PARP knock-out mice. 9,37,38 Cerebral ischemia results in massive activation of N-methyl-D-aspartat (NMDA) receptors via an increase of extracellular glutamate leading to elevated intracellular calcium concentrations, activation of neuronal NO synthase (nNOS), increased NO and ROS formation and ultimately to PARP-activating DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

2001

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Excessive activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by free-radical damaged DNA mediates necrotic cell death in injury models of cerebral ischemiareperfusion and excitotoxicity. We recently reported that secondary retinal ganglion cell (RGC) death following rat optic nerve (ON) transection is mainly apoptotic and can significantly but not entirely be blocked by caspase inhibition. In the present study, we demonstrate transient, RGC-specific PARP activation and increased retinal PARP expression early after ON axotomy. In addition, intravitreal injections of 3-aminobenzamide blocked PARP activation in RGCs and resulted in an increased number of surviving RGCs when compared to control animals 14 days after ON transection. These data indicate that secondary degeneration of a subset of axotomized RGCs results from a necrotic-type cell death mediated by PARP activation and increased PARP expression. Furthermore, PARP inhibition may constitute a relevant strategy for clinical treatment of traumatic brain injury. Cell Death and Differentiation (2001) 8, 801 ± 807.

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“…The possible mechanism of protection by hsp70 was studied by analysing the integrity of nuclear DNA as a major target for both NO and ROI cytotoxicity [6][7][8]. When DNA strand breaks were determined in individual cell nuclei by in situ nick translation it became apparent that hsp70 overexpression did not reduce the number of radical-damaged nuclei.…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein hsp70 overexpression confers resistance against nitric oxide

et al. 1996

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Heat stress is known to render rat islet cells resistant against the toxic effects of nitric oxide, reactive oxygen intermediates and the islet cell toxin streptozotocin. We report here for the first time that protection against nitric oxide is mediated by the major heat shock protein, hsp70, even in the absence of heat stress. The human hsp70 gene was stably transfected into the rat insulinoma cell line RINm5F. Constitutive expression of hsp70 caused protection from NO-induced cell lysis which was of the same extent as seen after heat stressing cells. Our results identify hsp70 as a defence molecule against nitric oxide.from the depressive effect of IL-1[~ on glucose-induced insulin secretion [18].These findings led us to hypothesize that among the different stress proteins expressed in heat stressed islet cells, hsp70 may confer protection against NO toxicity. To test this hypothesis we transfected a rat insulinoma cell line, RINm5F, with a vector containing the complete coding region of the human hspTO gene [10]. Analysis of the stably transfected clones revealed that hsp70 confers resistance against the cytotoxicity of NO.

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Nitric Oxide Toxicity in Islet Cells Involves Poly(ADP-Ribose) Polymerase Activation and Concomitant NAD+ Depletion

Cited by 182 publications

References 0 publications

Suppression of nitric oxide toxicity in islet cells by α‐tocopherol

Suppression of nitric oxide toxicity in islet cells by α‐tocopherol

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

Heat shock protein hsp70 overexpression confers resistance against nitric oxide

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