Partial protection by poly(ADP-ribose) polymerase inhibitors from nitroxyl-induced cytotoxicity in thymocytes

Péter Bai, Edina Bakondi, Éva Szabó, Pál Gergely, Csaba Szabó, László Virág

    Research output: Contribution to journalArticle

    40 Scopus citations

    Abstract

    Nitroxyl (NO-/HNO), has been proposed to be one of the NO-derived cytotoxic species. Although the biological effect of nitroxyl is largely unknown, it has been reported to cause DNA breakage and cytotoxicity. We have therefore investigated whether NO-/HNO-induced DNA single-strand breakage activates the nuclear nick sensor enzyme poly(ADP-ribose) polymerase (PARP) and whether PARP activation affects the mode of NO-/HNO- induced cell death. NO-/HNO generated from Angeli's salt (AS, sodium trioxodinitrate) (0-300 μM) induced DNA single-strand breakage, PARP activation, and a concentration-dependent cytotoxicity in murine thymocytes. AS-induced cell death was also accompanied by decreased mitochondrial membrane potential and increased secondary superoxide production. The cytotoxicity of AS, as measured by propidium iodide uptake, was abolished by electron acceptors potassium ferricyanide, TEMPOL, the intracellular calcium chelator BAPTA-AM, and by PARP inhibitors 3-aminobenzamide (3-AB) and PJ-34. The cytoprotective effect of 3-AB was paralleled by increased output of AS-induced apoptotic parameters such as phosphatidylserine exposure, caspase activation, and DNA fragmentation. No significant increase in tyrosine nitration could be observed in AS-treated thymocytes as opposed to peroxynitrite-treated cells, indicating that tyrosine nitration is not likely to contribute to NO-/HNO-induced cytotoxicity. Our results demonstrate that NO-/HNO-induced PARP activation shifts the default apoptotic cell death toward necrosis in thymocytes. However, as total PARP inhibition resulted only in 30% cytoprotection, PARP-independent mechanisms dominate NO-/HNO-induced cytotoxicity in thymocytes.

    Original languageEnglish (US)
    Pages (from-to)1616-1623
    Number of pages8
    JournalFree Radical Biology and Medicine
    Volume31
    Issue number12
    DOIs
    StatePublished - Dec 15 2001

    Keywords

    • Apoptosis
    • Free radicals
    • Necrosis
    • Nitric oxide
    • Nitroxyl
    • Poly(ADP-ribose) polymerase

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology (medical)

    Fingerprint Dive into the research topics of 'Partial protection by poly(ADP-ribose) polymerase inhibitors from nitroxyl-induced cytotoxicity in thymocytes'. Together they form a unique fingerprint.

  • Cite this