Poly(ADP-ribose) polymerase inhibition improves endothelial dysfunction induced by reactive oxidant hydrogen peroxide in vitro

Tamás Radovits, Li ni Lin, Julia Zotkina, Domokos Gero, Csaba Szabó, Matthias Karck, Gábor Szabó

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Reactive oxygen species, such as hydrogen peroxide (H2O2) induce oxidative stress and DNA-injury. The subsequent activation of poly(ADP-ribose) polymerase (PARP) has been implicated in the pathogenesis of various cardiovascular diseases including ischaemia-reperfusion injury, circulatory shock, diabetic complications and atherosclerosis. We investigated the effect of PARP-inhibition on endothelial dysfunction induced by H2O2. In vascular reactivity measurements on isolated rat aortic rings we investigated the phenylephrine-induced contraction, and endothelium-dependent and -independent vasorelaxation by using cumulative concentrations of acetylcholine and sodium nitroprusside. Endothelial dysfunction was induced by exposing the rings to H2O2 (200 and 400 μM) for 30 min. In the treatment group, rings were preincubated with the potent PARP-inhibitor INO-1001. DNA strand breaks were assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. Immunohistochemical analysis was performed for poly(ADP-ribose) (the enzymatic product of PARP) and for apoptosis inducing factor (a pro-apoptotic factor regulated by PARP). Exposure to H2O2 resulted in reduced contraction forces and a dose-dependent impairment of endothelium-dependent vasorelaxation of aortic rings (maximal relaxation to acetylcholine: 86.21 ± 1.574% control vs. 72.55 ± 1.984% H2O2 200 μM vs. 66.86 ± 1.961% H2O2 400 μM; P < 0.05). PARP-inhibition significantly improved the acetylcholine-induced vasorelaxation (77.75 ± 3.019% vs. 66.86 ± 1.961%; P < 0.05), while the contractility remained unaffected. The dose-response curves of endothelium-independent vasorelaxation to sodium nitroprusside did not differ in any groups studied. In the H2O2 groups immunohistochemical analysis showed enhanced PARP-activation and nuclear translocation of apoptosis inducing factor, which were prevented by INO-1001. Our results demonstrate that PARP activation contributes to the pathogenesis of H2O2-induced endothelial dysfunction, which can be prevented by PARP inhibitors.

Original languageEnglish
Pages (from-to)158-166
Number of pages9
JournalEuropean Journal of Pharmacology
Volume564
Issue number1-3
DOIs
Publication statusPublished - Jun 14 2007

Keywords

  • Apoptosis
  • Endothelial dysfunction
  • Hydrogen peroxide
  • Oxidative stress
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Pharmacology

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