Ablation of the heat shock factor-1 increases susceptibility to hyperoxia-mediated cellular injury.
High concentrations of oxygen (hyperoxia) are known to cause cellular injury and death. The heat shock response is a highly conserved cellular defense mechanism that protects cells against various environmental stressors, including hyperoxia. Herein we determined the role of heat shock factor-1 (HSF-1), a major component of the heat shock response, in protecting cells against hyperoxia. Embryonic fibroblasts from HSF-1-null mutant mice (HSF-1 -/- cells) were compared to wild-type embryonic fibroblasts (HSF-1 +/+ cells) following 24 hours' exposure to room air or hyperoxia (95% O(2)). Acute survival in hyperoxia was decreased in HSF-1 -/- cells as compared to HSF-1 +/+ cells. Intracellular ATP levels were significantly lower in the HSF-1 -/- cells as compared to the HSF-1 +/+ cells exposed to hyperoxia. Isoprostane levels, a marker of membrane lipid peroxidation, were significantly higher in the HSF-1 -/- cells as compared to the HSF-1 +/+ cells exposed to hyperoxia. Restoration of HSF-1 in the HSF-1 -/- cells by stable transfection with a HSF-1 expression plasmid improved survival in hyperoxia when compared to HSF-1 -/- cells stably transfected with the empty expression vector. Hyperoxia increased activation of HSF-1 in HSF-1 +/+ cells and in HSF-1 -/- cells stably transfected with the HSF-1 expression plasmid. These data demonstrate that HSF-1 plays an important role in conferring resistance to hyperoxia in vitro.
Malhotra
Vivek
V
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio 45229-3039, USA.
Kooy
Neil W
NW
Denenberg
Alvin G
AG
Dunsmore
Katherine E
KE
Wong
Hector R
HR
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D028421:Isoprostanes / Q000096:biosynthesis; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D014157:Transcription Factors; D014162:Transfection
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D028421:Isoprostanes; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D010100:Oxygen