Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite.

Szabó, Csaba; Cuzzocrea, Salvatore; Zingarelli, Basilia; O’Connor, Michael; Salzman, Andrew L.

doi:10.1172/jci119585

Cited by 362 publications

(234 citation statements)

References 64 publications

(96 reference statements)

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“…In endothelial cells treated with high glucose, as well as in diabetes and hyperglycaemia, a sequence of events has been proposed whereby reactive nitrogen and oxygen species trigger DNA single-strand breaks, which in turn induce the rapid and excessive activation of PARP, an event which quickly depletes the intracellular stores of NAD þ (Soriano et al, 2001;Virag & Szabo, 2002). This depletion slows glycolysis, electron transport and ATP formation, and finally initiates acute endothelial dysfunction and vascular instability (Eliasson et al, 1997;Szabo et al, 1997;Burkart et al, 1999;Pieper et al, 1999a;.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, poly(ADP-ribosyl)ation plays a key role in a number of physiological cellular functions including participation in DNA base-excision repair, resistance to genotoxic stress, regulation of genomic stability and gene expression, regulation of transcription and proteasomal function and apoptosis. However, in contrast to these cytoprotective functions, overstimulation of PARP is associated with pathophysiological effects resulting from rapid depletion of the intracellular NAD þ and ATP pools; this slows the rate of glycolysis and mitochondrial respiration and leads to cellular dysfunction (Eliasson et al, 1997;Szabo et al, 1997;Zingarelli et al, 1998;Burkart et al, 1999;Oliver et al, 1999;Pieper et al, 1999a, b;Soriano et al, 2001). PARP activation is implicated in the pathogenesis of stroke (Eliasson et al, 1997), autoimmune b-cell destruction (Burkart et al, 1999;Pieper et al, 1999a), shock and inflammation (Szabo et al, 1997;Oliver et al, 1999) and diabetic vascular dysfunction (Soriano et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

Crocker

Kenny

Thornton

et al. 2005

British J Pharmacology

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1 Pre-eclampsia is a serious pregnancy disorder associated with widespread activation of the maternal vascular endothelium. Recent evidence implicates a role for oxidative stress in the aetiology of this condition. 2 Reactive oxygen species, particularly superoxide anions, invokes endothelial cell activation through many pathways. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes). 3 We have studied whether the loss of endothelial function in pre-eclampsia is dependent on PARP activity. Endothelium-dependent responses of myometrial arteries were tested following exposure to either plasma from women with pre-eclampsia or normal pregnant women in the presence and absence of a novel potent inhibitor of PARP, PJ34. Additional effects of plasma and PJ34 inhibition were identified in microvascular endothelial cell cultures. 4 In myometrial arteries, PARP inhibition blocked the attenuation of endothelium-dependent responses following exposure to plasma from women with pre-eclampsia. In endothelial cell cultures, plasma from pre-eclamptics induced measurable oxidative stress and a concomitant increase in PARP activity and reduction in cellular ATP. Again, these biochemical changes were reversed by PJ34. 5 These results suggest that PARP activity plays a pathogenic role in the development of endothelial dysfunction in pre-eclampsia and promotes PARP inhibition as a potential therapy in this condition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

Crocker

Kenny

Thornton

et al. 2005

British J Pharmacology

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“…First, peroxynitrite is produced in large amounts on reperfusion [16]. Second, the cytotoxic effect of peroxynitrite toward the vascular endothelium has been directly demonstrated in perfused hearts [29] and in cultured human umbilical vein endothelial cells [30]. Third, in the presence of superoxide generators, agonist-induced release of NO from ecNOS exerts autocrine cytotoxic effects via the generation of peroxynitrite, which can be prevented by inhibition of endothelial NOS in vitro [31].…”

Section: Discussionmentioning

confidence: 99%

IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock

Cuzzocrea

Sarro

Costantino

et al. 1999

Journal of Leukocyte Biology

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We used IL-6 knock-out (KO) mice to evaluate a possible role for IL-6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO-shocked IL-6 wild-type (WT) mice after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL-6 WT mice. SAO-shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin. Little specific staining was observed in sham-WT mice. Staining of ileum tissue obtained from sham-operated WT mice with anti-ICAM-1 antibody showed weak but diffuse staining, demonstrating that ICAM-1 is constitutively expressed. However, after SAO shock the staining intensity increased substantially in the ileum section from WT mice. Intensity and degree of Pselectin and ICAM-1 were markedly reduced in tissue section from SAO-shocked IL-6 KO mice. SAO-shocked IL-6 KO mice also show significant reduction of neutrophil infiltration into the reperfused intestine, as evidenced by reduced MPO activity, improved histological status of the reperfused tissues, reduced peroxynitrite formation, reduced MDA levels, and improved survival. In vivo treatment with anti-IL-6 significantly prevents the inflammatory process. Our results clearly demonstrate that IL-6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL-6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury. J. Leukoc. Biol. 66: 471-480; 1999.

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“…On the other hand, overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury (Zingarelli et al 1998), heart transplantation , heart failure (Pacher et al 2002b, c), stroke (Eliasson et al 1997), circulatory shock (Szabó et al 1997a, Oliver et al 1999, Jagtap et al 2002, Shimoda et al 2003, and autoimmune beta-cell destruction associated with diabetes mellitus (Burkart et al 1999, Pieper et al 1999. Activation of PARP and beneficial effects of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia and aging (Szabó et al 1997, Hung et al 2002, Martinet et al 2002.…”

Section: Poly(adp-ribose) Polymerase and Its Activationmentioning

confidence: 99%

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Kiss

Szabó

2005

Mem. Inst. Oswaldo Cruz

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Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite.

Cited by 362 publications

References 64 publications

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

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