Role of zinc in pulmonary endothelial cell response to oxidative stress.
Although zinc is a well-known inhibitor of apoptosis, it may contribute to oxidative stress-induced necrosis. We noted that N,N,N',N'- tetrakis(2-pyridylmethyl)ethylenediamine (TPEN; >10 microM), a zinc chelator, quenched fluorescence of the zinc-specific fluorophore Zinquin and resulted in an increase in spontaneous apoptosis in cultured sheep pulmonary artery endothelial cells (SPAECs). Addition of exogenous zinc (in the presence of pyrithione, a zinc ionophore) to the medium of SPAECs caused an increase in Zinquin fluorescence and was associated with a concentration-dependent increase in necrotic cell death. Exposure of SPAECs to TPEN (10 microM) resulted in enhanced apoptosis after lipopolysaccharide or complete inhibition of t-butyl hydroperoxide (tBH)-induced necrosis. We further investigated the role of two zinc-dependent enzymes, poly(ADP-ribose) polymerase (PARP) and protein kinase (PK) C, in tBH toxicity. tBH toxicity was only affected by the PARP inhibitors 4-amino-1,8-naphthalimide or 3-aminobenzamide over a narrow range, whereas the PKC inhibitors bisindolylmaleimide and staurosporine significantly reduced tBH toxicity. tBH caused translocation of PKC to the plasma membrane of SPAECs that was partially inhibited by TPEN. Thus pulmonary endothelial cell zinc inhibits spontaneous and lipopolysaccharide-dependent apoptosis but contributes to tBH-induced necrosis, in part, via a PKC-dependent pathway.
Tang
Z L
ZL
Department of Environmental and Occupational Health, The Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Wasserloos
K
K
St  Croix
C M
CM
Pitt
B R
BR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009336:Necrosis; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D012756:Sheep; D015032:Zinc / Q000494:pharmacology / Q000502:physiology*; D020122:tert-Butylhydroperoxide / Q000506:poisoning
D008070:Lipopolysaccharides; D020122:tert-Butylhydroperoxide; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D015032:Zinc