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

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 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 microM). 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.

Anti-inflammatory mechanism of taurine against ischemic stroke is related to down-regulation of PARP and NF-κB

“…c The bar graph reflects the cell death score in the penumbra and core in each group (mean ± SEM; n = 7; *P \ 0.05 and **P \ 0.01 vs. vehicle) Deby-Dupont et al 1999). HOCl has been reported to induce neuronal death and endothelial dysfunction in vitro (Yap et al 2006;Radovits et al 2007). Moreover, MPO activation is detrimental during experimental stroke (Miljkovic-Lolic et al 2003), and it is used to evaluate the infiltration of neutrophils in the rodent model of ischemic stroke (Barone et al 1991;Matsuo et al 1994).…”

Endothelial Dysfunction After Long-term Cold Storage in HTK Organ Preservation Solutions: Effects of Iron Chelators and N-α-acetyl-l-histidine

“…18,23,24 Mainly endothelial nitric oxide production-and, to a lesser extent, the endothelium-derived hyperpolarizing factor-mediated function-becomes impaired during ischemic preservation and reperfusion. 25,26 Impairment of endothelial function (reduced endothelium-dependent vasorelaxation) in the coronary arteries may lead to regional or global myocardial ischemia, which further impairs cardiac performance after transplantation.…”

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…For instance, inhibition or deletion of PARP inhibits the activation of MAP kinases, AP-1 and NF-κB, which, in turn, suppresses the expression of various pro-inflammatory genes, including TNF-α, the inducible NO synthase and intercellular adhesion molecule-1 (Zingarelli et al, 1999;Zingarelli et al, 2003;Song et al, 2013). A third mechanism of cardiac protection by PARP inhibitors may be related to maintenance of endothelial integrity and endothelial function, either by direct protective effects -because PARP activation, in response to various forms of oxidative insults, induces endothelial dysfunction (Garcia Soriano et al, 2001;Radovits et al, 2007;Horváth et al, 2009;Módis et al, 2012) -or by secondary effects involving the inhibition of adhesion, activation and tissue infiltration of various mononuclear and polymorphonuclear cell types into the myocardium . All of the above processes may also influence each other in a variety of ways, forming a positive feed-forward network of myocardial injury (see Jagtap and Szabó, 2005).…”