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

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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
Pages (from-to)1204-1212
Number of pages9
JournalExperimental Biology and Medicine
Volume232
Issue number9
DOIs
Publication statusPublished - Oct 1 2007

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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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