title: Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.
abstract: Peroxisome proliferator-activated receptor-α is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-α null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-α in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-α confers a survival advantage.
  
  
  
  Prospective randomized preclinical study.
  
  
  
  Laboratory investigation.
  
  
  
  Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.
  
  
  
  Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.
  
  
  
  Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-α status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.
  
  
  
  Peroxisome proliferator-activated receptor-α expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-α expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-α-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.
authors.affiliation: 1Center for Lung Biology, Department of Medicine, University of Washington School of Medicine, Seattle, WA. 2Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, WA. 3Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA. 4Department of Medicine, University of Washington School of Medicine, Seattle, WA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Standage
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Waworuntu
authors.forename: Martha A
authors.initials: MA
authors.lastname: Delaney
authors.forename: Sara M
authors.initials: SM
authors.lastname: Maskal
authors.forename: Brock G
authors.initials: BG
authors.lastname: Bennion
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: John K
authors.initials: JK
authors.lastname: McGuire
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001786:Blood Glucose; D001835:Body Weight; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D015536:Down-Regulation; D015870:Gene Expression; D006304:Health Status; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics*; D011446:Prospective Studies; D011897:Random Allocation; D018805:Sepsis / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology; D019210:Troponin I / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D047493:PPAR alpha; D019210:Troponin I