title: PCB-induced endothelial cell dysfunction: role of poly(ADP-ribose) polymerase.
abstract: Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2',4,6,6'-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.
authors: Brighton and Sussex Medical School, Falmer, Brighton BN1 9PH, UK.
authors: Simon G
authors: SG
authors: Helyar
authors: Bella
authors: B
authors: Patel
authors: Kevin
authors: K
authors: Headington
authors: Mary
authors: M
authors: El Assal
authors: Prabal K
authors: PK
authors: Chatterjee
authors: Pal
authors: P
authors: Pacher
authors: Jon G
authors: JG
authors: Mabley
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004785:Environmental Pollutants / Q000737:chemistry / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D016877:Oxidants / Q000009:adverse effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D007202:Indicators and Reagents; D016877:Oxidants; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009580:Nitroblue Tetrazolium; D009569:Nitric Oxide; D009249:NADP; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D011065:Poly(ADP-ribose) Polymerases; D000109:Acetylcholine; C417207:2,2',4,6,6'-pentachlorobiphenyl