Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by hypochlorite

Tamás Radovits, Julia Zotkina, Li Ni Lin, Timo Bömicke, Rawa Arif, Domokos Gero, Eszter M. Horváth, Matthias Karck, Csaba Szabó, Gábor Szabó

    Research output: Contribution to journalArticle

    19 Scopus citations

    Abstract

    Reactive oxygen species, such as myeloperoxidase-derived hypochlorite, induce oxidative stress and DNA injury. The subsequent activation of the DNA-damage-poly(ADP-ribose) polymerase (PARP) pathway has been implicated in the pathogenesis of various diseases, including ischemia-reperfusion injury, circulatory shock, diabetic complications, and atherosclerosis. We investigated the effect of PARP inhibition on the impaired endothelium-dependent vasorelaxation induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endotheliumindependent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside. Endothelial dysfunction was induced by exposing rings to hypochlorite (100-400 μM). In the treatment group, rings were preincubated with the PARP inhibitor INO-1001. DNA strand breaks were assessed by the TUNEL method. Immunohistochemistry was performed for 4-hydroxynonenal (a marker of lipid peroxidation), nitrotyrosine (a marker of nitrosative stress), and poly(ADP-ribose) (an enzymatic product of PARP). Exposure to hypochlorite resulted in a dose-dependent impairment of endothelium-dependent vasorelaxation of aortic rings, which was significantly improved by PARP inhibition, whereas the endothelium-independent vasorelaxation remained unaffected. In the hypochlorite groups we found increased DNA breakage, lipidperoxidation, and enhanced nitrotyrosine formation. The hypochloride-induced activation of PARP was prevented by INO-1001. Our results demonstrate that PARP activation contributes to the pathogenesis of hypochlorite-induced endothelial dysfunction, which can be prevented by PARP inhibitors.

    Original languageEnglish (US)
    Pages (from-to)1204-1212
    Number of pages9
    JournalExperimental Biology and Medicine
    Volume232
    Issue number9
    DOIs
    StatePublished - Oct 1 2007

    Keywords

    • DNA injury
    • Endothelial dysfunction
    • Hypochlorite
    • Oxidative stress
    • Poly(ADP-ribose) polymerase

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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    Radovits, T., Zotkina, J., Lin, L. N., Bömicke, T., Arif, R., Gero, D., Horváth, E. M., Karck, M., Szabó, C., & Szabó, G. (2007). Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by hypochlorite. Experimental Biology and Medicine, 232(9), 1204-1212. https://doi.org/10.3181/0701-RM-16