Peroxynitrite causes energy depletion and increases permeability via activation of poly (ADP-ribose) synthetase in pulmonary epithelial cells.
Recent studies show that peroxynitrite is a potent trigger of DNA strand breakage, which in turn activates the nuclear repair enzyme poly (ADP-ribose) synthetase (PARS), resulting in a cellular energy deficit. Here we present evidence that treatment of A549 human pulmonary epithelial cells with peroxynitrite (1 mM) results in ADP-ribosylation, NAD+ depletion, inhibition of mitochondrial respiration, and increased epithelial paracellular permeability. The PARS inhibitor 3-aminobenzamide (1 mM) provided a significant, partial protection against the energetic and functional changes. Similarly, inhibition of PARS activity by 3-aminobenzamide reduced the peroxynitrite-induced suppression of mitochondrial respiration in BEAS-2B human bronchial epithelial cells. Thus, PARS activation and energy depletion represents one of the pathways of peroxynitrite-mediated epithelial toxicity. Inhibition of PARS may improve cellular energy homeostasis in pathophysiologic conditions associated with peroxynitrite generation.
Szabó
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Division of Critical Care, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Saunders
C
C
O'Connor
M
M
Salzman
A L
AL
D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004734:Energy Metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009566:Nitrates / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D001549:Benzamides; D004791:Enzyme Inhibitors; D009566:Nitrates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C039642:peroxynitric acid; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases