Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells

M. Kennedy, A. G. Denenberg, Csaba Szabo, A. L. Salzman, S. P. Colgan

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Abstract

Background and Aims: Peroxynitrite induces cytotoxicity by generating DNA single-strand breaks and activating poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that consumes oxidized nicotinamide adenine dinucleotide (NAD+) and depletes cellular adenosine triphosphate (ATP). The aim of this study was to examine this mechanism of injury in an intestinal epithelial cell model after exposure to exogenous peroxynitrite (ONOO-) and nitric oxide (NO). Methods: Caco-2BBe cell monolayers exposed to donors of peroxynitrite (3-morpholino-sydnonimine [SIN-1], 3 mmol/L) or NO (S-nitroso- N-acetyl penicillamine [SNAP]; 3 mmol/L) were analyzed for DNA strand breaks, [NAD+], [ATP], and transepithelial flux of fluorescein sulfonic acid. Results: SIN-1 but not SNAP induced DNA single-strand breakage. Both SIN-1 and SNAP reduced [ATP], but only SIN-1 reduced [NAD+]. Inhibition of PARS activity by the PARS inhibitors 5-iodo-6-amino 1,2-benzopyrone or 3- aminobenzamide prevented the SIN-1-induced reduction in [NAD+] and [ATP] but had no effect on the SNAP-induced reduction in [ATP]. PARS inhibition reduced SIN-1-but not SNAP-induced hyperpermeability. Conclusions: Peroxynitrite but not NO increases transepithelial permeability by inducing DNA strand breaks that activate the PARS pathway and cause the depletion of intracellular energy stores. Inhibition of PARS activity may represent a novel strategy in ameliorating peroxynitrite-mediated epithelial injury during intestinal inflammation.

Original languageEnglish (US)
JournalGastroenterology
Volume114
Issue number3
DOIs
StatePublished - 1998
Externally publishedYes

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Poly Adenosine Diphosphate Ribose
Peroxynitrous Acid
Ligases
Penicillamine
Permeability
NAD
Adenosine Triphosphate
Nitric Oxide
DNA Breaks
Single-Stranded DNA Breaks
Wounds and Injuries
Epithelial Cells
Inflammation
DNA
Enzymes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells. / Kennedy, M.; Denenberg, A. G.; Szabo, Csaba; Salzman, A. L.; Colgan, S. P.

In: Gastroenterology, Vol. 114, No. 3, 1998.

Research output: Contribution to journalArticle

Kennedy, M. ; Denenberg, A. G. ; Szabo, Csaba ; Salzman, A. L. ; Colgan, S. P. / Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells. In: Gastroenterology. 1998 ; Vol. 114, No. 3.
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abstract = "Background and Aims: Peroxynitrite induces cytotoxicity by generating DNA single-strand breaks and activating poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that consumes oxidized nicotinamide adenine dinucleotide (NAD+) and depletes cellular adenosine triphosphate (ATP). The aim of this study was to examine this mechanism of injury in an intestinal epithelial cell model after exposure to exogenous peroxynitrite (ONOO-) and nitric oxide (NO). Methods: Caco-2BBe cell monolayers exposed to donors of peroxynitrite (3-morpholino-sydnonimine [SIN-1], 3 mmol/L) or NO (S-nitroso- N-acetyl penicillamine [SNAP]; 3 mmol/L) were analyzed for DNA strand breaks, [NAD+], [ATP], and transepithelial flux of fluorescein sulfonic acid. Results: SIN-1 but not SNAP induced DNA single-strand breakage. Both SIN-1 and SNAP reduced [ATP], but only SIN-1 reduced [NAD+]. Inhibition of PARS activity by the PARS inhibitors 5-iodo-6-amino 1,2-benzopyrone or 3- aminobenzamide prevented the SIN-1-induced reduction in [NAD+] and [ATP] but had no effect on the SNAP-induced reduction in [ATP]. PARS inhibition reduced SIN-1-but not SNAP-induced hyperpermeability. Conclusions: Peroxynitrite but not NO increases transepithelial permeability by inducing DNA strand breaks that activate the PARS pathway and cause the depletion of intracellular energy stores. Inhibition of PARS activity may represent a novel strategy in ameliorating peroxynitrite-mediated epithelial injury during intestinal inflammation.",
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AB - Background and Aims: Peroxynitrite induces cytotoxicity by generating DNA single-strand breaks and activating poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that consumes oxidized nicotinamide adenine dinucleotide (NAD+) and depletes cellular adenosine triphosphate (ATP). The aim of this study was to examine this mechanism of injury in an intestinal epithelial cell model after exposure to exogenous peroxynitrite (ONOO-) and nitric oxide (NO). Methods: Caco-2BBe cell monolayers exposed to donors of peroxynitrite (3-morpholino-sydnonimine [SIN-1], 3 mmol/L) or NO (S-nitroso- N-acetyl penicillamine [SNAP]; 3 mmol/L) were analyzed for DNA strand breaks, [NAD+], [ATP], and transepithelial flux of fluorescein sulfonic acid. Results: SIN-1 but not SNAP induced DNA single-strand breakage. Both SIN-1 and SNAP reduced [ATP], but only SIN-1 reduced [NAD+]. Inhibition of PARS activity by the PARS inhibitors 5-iodo-6-amino 1,2-benzopyrone or 3- aminobenzamide prevented the SIN-1-induced reduction in [NAD+] and [ATP] but had no effect on the SNAP-induced reduction in [ATP]. PARS inhibition reduced SIN-1-but not SNAP-induced hyperpermeability. Conclusions: Peroxynitrite but not NO increases transepithelial permeability by inducing DNA strand breaks that activate the PARS pathway and cause the depletion of intracellular energy stores. Inhibition of PARS activity may represent a novel strategy in ameliorating peroxynitrite-mediated epithelial injury during intestinal inflammation.

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