title: Glutamine-mediated attenuation of cellular metabolic dysfunction and cell death after injury is dependent on heat shock factor-1 expression.
abstract: BACKGROUND
  Cellular metabolic dysfunction is associated with occurrence of multiple-organ failure after critical illness. Glutamine (GLN) attenuates cellular metabolic dysfunction in critical illness models. The mechanism of this protection is unclear. We previously demonstrated that GLN's benefit in critical illness might be due to enhanced heat shock protein (HSP) expression. We hypothesize that GLN's attenuation of cellular metabolic dysfunction is dependent on presence of heat shock factor-1 (HSF-1).
  
  
  METHODS
  HSF-1 wild-type and knockout mouse embryonic fibroblasts (HSF-1+/+ and HSF-1-/-) were used in all experiments. Cells were not treated, or were treated with 8 mmol/L GLN and immediately exposed to heat stress injury (45 degrees C for 45 minutes). Cells were harvested for metabolic analysis by nuclear magnetic resonance (NMR) at 24 hours postinjury. Cell survival was assessed using the MTS assay.
  
  
  RESULTS
  GLN treatment in HSF-1+/+ cells led to significant attenuation of decreases in adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, phosphomonoester/phosphodiester (PME/PDE) ratio, and cell survival observed in non-GLN-treated HSF-1+/+ cells. In HSF-1-/- cells, the beneficial effect of GLN on preservation of ATP/ADP ratio, PME/PDE proliferation, and cell survival was lost. GLN-treated HSF-1-/- cells had a significant increase in extracellular lactate concentrations vs GLN-treated HSF+/+ cells.
  
  
  CONCLUSIONS
  GLN treatment attenuated cellular metabolic dysfunction and improved cell membrane recovery only in HSF-1+/+ cells. Cellular injury, as measured by lactate release and cell survival assay, was improved by GLN treatment in HSF-1+/+ cells alone. Thus, GLN's beneficial effect on cellular metabolic dysfunction and cell survival appears to be dependent on HSF-1 expression.
authors.affiliation: Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, 80262, USA.
authors.forename: Zhi Yong
authors.initials: ZY
authors.lastname: Peng
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Jaimi L
authors.initials: JL
authors.lastname: Brown
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016638:Critical Illness / Q000628:therapy; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D005973:Glutamine / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology*; D006358:Hot Temperature / Q000009:adverse effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D005973:Glutamine