Hypoxia renders hepatocytes susceptible to cell death by nitric oxide.
Under normoxic conditions, nitric oxide (NO) suppresses hepatocyte apoptosis. In contrast, NO contributes to hepatocellular injury in conditions associated with ischemia and reperfusion. To understand this paradoxical effect further, we compared the effects of various doses of NO, delivered from the chemical NO donor S-nitroso-N-acetylpenicillamine (SNAP), under both normoxic and hypoxic tissue culture conditions. We found that the cell death induced by NO under hypoxic conditions, which increased the production of reactive oxygen species, was accompanied by a necrotic morphology with a concomitant early decrease in ATP levels. The NO-induced death of hypoxic hepatocytes was reversed by co-incubation with the anti-oxidant N-acetylcysteine. We conclude that hypoxia-induced oxidative stress subsequent to ATP depletion can switch NO from an anti-apoptotic to a hepatotoxic agent. These findings may have implications for NO-induced liver damage in settings of tissue hypoxia.
Kim
P K M
PK
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. kimp@upmc.edu
Vallabhaneni
R
R
Zuckerbraun
B S
BS
McCloskey
C
C
Vodovotz
Y
Y
Billiar
T R
TR
D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology
D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D010396:Penicillamine; D000111:Acetylcysteine