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

Ian P. Crocker, Louise C. Kenny, Wayne A. Thornton, Csaba Szabo, Philip N. Baker

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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. 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). 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. 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. 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.

Original languageEnglish
Pages (from-to)772-780
Number of pages9
JournalBritish Journal of Pharmacology
Volume144
Issue number6
DOIs
StatePublished - Mar 2005
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Pre-Eclampsia
Adenosine Diphosphate
Endothelial Cells
Endothelium
Oxidative Stress
Arteries
Cell Culture Techniques
Enzyme Activation
Vascular Endothelium
Oxidants
Superoxides
Reperfusion
Pregnant Women
Shock
Reactive Oxygen Species
Adenosine Triphosphate
Mothers
Pregnancy
Wounds and Injuries

Keywords

  • Endothelium
  • Poly(ADP-ribose) polymerase
  • Pre-eclampsia
  • Pregnancy

ASJC Scopus subject areas

  • Pharmacology

Cite this

Excessive stimulation of poly(ADP-ribosyl)ation contributes to endothelial dysfunction in pre-eclampsia. / Crocker, Ian P.; Kenny, Louise C.; Thornton, Wayne A.; Szabo, Csaba; Baker, Philip N.

In: British Journal of Pharmacology, Vol. 144, No. 6, 03.2005, p. 772-780.

Research output: Contribution to journalArticle

Crocker, Ian P. ; Kenny, Louise C. ; Thornton, Wayne A. ; Szabo, Csaba ; Baker, Philip N. / Excessive stimulation of poly(ADP-ribosyl)ation contributes to endothelial dysfunction in pre-eclampsia. In: British Journal of Pharmacology. 2005 ; Vol. 144, No. 6. pp. 772-780.
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