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ORIGINAL RESEARCH ARTICLE

Poly(ADP-Ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hypochlorite

Tamás Radovits^*,,1, Julia Zotkina^*, Li-Ni Lin^*, Timo Bömicke^*, Rawa Arif^*, Domokos Gerö, Eszter M. Horváth, Matthias Karck^*, Csaba Szabó^, and Gábor Szabó^*

^* Department of Cardiac Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Department of Cardiovascular Surgery, Semmelweis University, 1122 Budapest, Hungary; CellScreen Applied Research Center, Semmelweis University, 1091 Budapest, Hungary; and Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

To whom requests for reprints should be addressed at ¹ The Laboratory of Cardiac Surgery Department of Cardiac Surgery, University of Heidelberg, INF 326. 2. OG., 69120 Heidelberg, Germany. E-mail: radovitstamas{at}yahoo.com

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 endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitro-prusside. 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.

Key Words: hypochlorite • oxidative stress • DNA injury • poly(ADP-ribose) polymerase • endothelial dysfunction