title: PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.
abstract: Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara-/-) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara-/-mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara-/-mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara-/-mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality.
  In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.
authors.affiliation: Center for Lung Biology, University of Washington School of Medicine, Seattle, Washington; sws24@uw.edu.|Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, Washington.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Standage
authors.affiliation: Center for Lung Biology, University of Washington School of Medicine, Seattle, Washington.|Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, Washington.
authors.forename: Brock G
authors.initials: BG
authors.lastname: Bennion
authors.affiliation: Center for Lung Biology, University of Washington School of Medicine, Seattle, Washington.|Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, Washington.
authors.forename: Taft O
authors.initials: TO
authors.lastname: Knowles
authors.affiliation: Department of Pediatrics (Cardiology), University of Washington School of Medicine, Seattle, Washington.|Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Dolena R
authors.initials: DR
authors.lastname: Ledee
authors.affiliation: Department of Pediatrics (Cardiology), University of Washington School of Medicine, Seattle, Washington.|Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
authors.affiliation: Center for Lung Biology, University of Washington School of Medicine, Seattle, Washington.|Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, Washington.
authors.forename: John K
authors.initials: JK
authors.lastname: McGuire
authors.affiliation: Center for Lung Biology, University of Washington School of Medicine, Seattle, Washington.|Department of Medicine, University of Washington School of Medicine, Seattle, Washington; and.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Department of Pediatrics (Cardiology), University of Washington School of Medicine, Seattle, Washington.|Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Olson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002247:Carbon Isotopes; D002432:Cecum / Q000601:surgery; D002952:Citric Acid Cycle; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism*; D015151:Immunoblotting; D000067268:Isolated Heart Preparation; D008026:Ligation; D050356:Lipid Metabolism / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics*; D011677:Punctures; D019289:Pyruvic Acid / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000503:physiopathology
chemical_list: D002247:Carbon Isotopes; D005227:Fatty Acids; D047493:PPAR alpha; D019289:Pyruvic Acid
keywords: PPARα; cardiovascular failure; sepsis; septic shock