title: Patterns of gene expression associated with recovery and injury in heat-stressed rats.
abstract: BACKGROUND
  The in vivo gene response associated with hyperthermia is poorly understood. Here, we perform a global, multiorgan characterization of the gene response to heat stress using an in vivo conscious rat model.
  
  
  RESULTS
  We heated rats until implanted thermal probes indicated a maximal core temperature of 41.8°C (Tc,Max). We then compared transcriptomic profiles of liver, lung, kidney, and heart tissues harvested from groups of experimental animals at Tc,Max, 24 hours, and 48 hours after heat stress to time-matched controls kept at an ambient temperature. Cardiac histopathology at 48 hours supported persistent cardiac injury in three out of six animals. Microarray analysis identified 78 differentially expressed genes common to all four organs at Tc,Max. Self-organizing maps identified gene-specific signatures corresponding to protein-folding disorders in heat-stressed rats with histopathological evidence of cardiac injury at 48 hours. Quantitative proteomics analysis by iTRAQ (isobaric tag for relative and absolute quantitation) demonstrated that differential protein expression most closely matched the transcriptomic profile in heat-injured animals at 48 hours. Calculation of protein supersaturation scores supported an increased propensity of proteins to aggregate for proteins that were found to be changing in abundance at 24 hours and in animals with cardiac injury at 48 hours, suggesting a mechanistic association between protein misfolding and the heat-stress response.
  
  
  CONCLUSIONS
  Pathway analyses at both the transcript and protein levels supported catastrophic deficits in energetics and cellular metabolism and activation of the unfolded protein response in heat-stressed rats with histopathological evidence of persistent heat injury, providing the basis for a systems-level physiological model of heat illness and recovery.
authors.affiliation: Environmental Health Program, U,S, Army Center for Environmental Health Research, Bldg, 568 Doughten Drive, MD 21702-5010 Fort Detrick, Maryland. jonathan.d.stallings.mil@mail.mil.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Ippolito
authors.forename: Vineet
authors.initials: V
authors.lastname: Rakesh
authors.forename: Christine E
authors.initials: CE
authors.lastname: Baer
authors.forename: William E
authors.initials: WE
authors.lastname: Dennis
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Helwig
authors.forename: David A
authors.initials: DA
authors.lastname: Jackson
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Leon
authors.forename: John A
authors.initials: JA
authors.lastname: Lewis
authors.forename: Jaques
authors.initials: J
authors.lastname: Reifman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D009202:Cardiomyopathies / Q000209:etiology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018882:Heat Stress Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018869:Heat-Shock Response / Q000235:genetics*; D006358:Hot Temperature; D008297:Male; D008954:Models, Biological; D017510:Protein Folding; D040901:Proteomics; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome; D056811:Unfolded Protein Response