Excessive stimulation of poly(ADP-ribosyl)ation contributes to endothelial dysfunction in pre-eclampsia.
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.
Crocker
Ian P
IP
Maternal and Fetal Health Research Centre, University of Manchester, St Mary's Hospital, Whitworth Park, Manchester M13 0JH. Ian.Crocker@man.ac.uk
Kenny
Louise C
LC
Thornton
Wayne A
WA
Szabo
Csaba
C
Baker
Philip N
PN
D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001158:Arteries / Q000187:drug effects; D016022:Case-Control Studies; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D003470:Culture Media / Q000032:analysis / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008875:Middle Aged; D009215:Myometrium / Q000098:blood supply; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology; D010949:Plasma / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology
D000911:Antibodies, Monoclonal; D003470:Culture Media; D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C002744:3-nitrotyrosine; D014443:Tyrosine; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases