A key role for heme oxygenase-1 in nitric oxide resistance in murine motor neurons and glia.
Nitric oxide is utilized at low levels for intercellular signaling, and at high levels as a cytotoxic weapon during inflammation. Cellular NO resistance can be increased by prior exposure to sublethal NO levels to induce defense gene expression (adaptive NO resistance), which has been correlated with increased expression of heme oxygenase-1 (HO1) and was blocked by a heme oxygenase inhibitor. However, the possibility remained that other activities were affected by the inhibitor. To address this question, we conducted a genetic study of the HO1 role. We show here that primary cultures of spinal motor neurons and glia from homozygous HO1-null mice are strikingly more sensitive to NO cytotoxicity than are cells expressing HO1. Following an exposure to NO, the HO1-deficient cells were much more prone to apoptosis than were HO1-expressing cells with either one or two copies of a functional HO1 gene. These results confirm the in vivo role of HO1 as a front-line defense against NO toxicity in neuronal cells.
Bishop
Amy
A
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. bishopa@uah.edu
Yet
Shaw-Fang
SF
Lee
Mu-En
ME
Perrella
Mark A
MA
Demple
Bruce
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000502:physiology; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000633:toxicity; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D026361:Reactive Nitrogen Species / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D026361:Reactive Nitrogen Species; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse