Carbon monoxide mediates protection against nitric oxide toxicity in HeLa cells.
Nitric oxide (NO) mediates cell signaling at low (nanomolar) concentrations, but can be cytotoxic at higher concentrations. Heme oxygenase-1 (HO-1), implicated in a role in NO resistance, might confer its protective effect through the direct products biliverdin and CO or the secondary product bilirubin. We have therefore tested whether biliverdin, bilirubin, or CO can provide resistance to NO toxicity. HeLa cells treated with bilirubin or biliverdin (up to 25 microM) had unchanged survival of an NO challenge (1 mM spermine-NONOate or 2 mM DEA-NO), although they displayed increased resistance to H2O2 (350 microM). In contrast, prior exposure to CO (up to 100 ppm) increased NO resistance. An interval between CO exposure and NO resistance was required for the increased NO resistance. Because the CO-activated NO resistance was also blocked by the transcription inhibitor actinomycin D, inducible gene expression seems critical for the cytoprotection elicited by CO. Experiments in the presence of HO and guanylate cyclase inhibitors indicated that HO activity and cGMP signaling are not essential for the CO-protective effect. Last, inhibition of p38 MAPK activation fully blocked the CO-protective effect, indicating the involvement of this signaling pathway(s) in the CO response.
Reiter
Tiffany A
TA
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue 1-512, Boston, MA 02115, USA.
Demple
Bruce
B
D001663:Bilirubin / Q000494:pharmacology; D001664:Biliverdine / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D019384:Nucleic Acid Synthesis Inhibitors; D003609:Dactinomycin; D009569:Nitric Oxide; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; D001664:Biliverdine; D001663:Bilirubin