title: Activation of peroxisome proliferator-activated receptor-alpha by fenofibrate prevents myocardial dysfunction during endotoxemia in rats.
abstract: OBJECTIVE
  To investigate the effects of fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, on cardiac function in a rat endotoxemia model.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Three-month-old male Wistar rats.
  
  
  METHODS
  Animals were fed with standard diet containing no drug or fenofibrate (0.2%) for 14 days. They were then injected intravenously with either 5 mg/kg lipopolysaccharide (LPS and fenofibrate + LPS groups) or saline (control and fenofibrate groups).
  
  
  RESULTS
  In the LPS group, body weight loss, metabolic acidosis, and thrombocytopenia confirmed presence of systemic endotoxemia. LPS administration resulted in an early peak in plasma tumor necrosis factor-alpha, decreased cardiac contractility (isolated and perfused heart), reduced myofilament Ca2+ sensitivity (Triton-skinned cardiac fibers), and increased left ventricular nitric oxide (NO) end-oxidation products (NO(x) and NO2), without evidence of myocardial oxidative stress (thiobarbituric acid-reactive substances and antioxidant enzyme activities). Fenofibrate pretreatment (fenofibrate + LPS group) did not alter signs of endotoxemia but prevented reductions in both cardiac contractility and myofilament Ca2+ sensitivity. The peak of plasma tumor necrosis factor-alpha was attenuated, whereas myocardial NO(x) and NO2 remained similar to the LPS group. Oxidative stress was suggested from moderate increase in cardiac thiobarbituric acid-reactive substances and reduced glutathione peroxidase activity.
  
  
  CONCLUSIONS
  Fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, may prevent endotoxemia-induced cardiac dysfunction and reduction in myofilament Ca2+ sensitivity. Our data also suggest a mediating role for early peak plasma tumor necrosis factor-alpha, but not for myocardial NO production or oxidative stress.
authors.affiliation: Laboratoire de Pharmacologie, Faculté de Médecine, Université Lille II, Lille, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Jozefowicz
authors.forename: Hélène
authors.initials: H
authors.lastname: Brisson
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rozenberg
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.forename: Patrick
authors.initials: P
authors.lastname: Gelé
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.forename: Gilles
authors.initials: G
authors.lastname: Lebuffe
authors.forename: Benoît
authors.initials: B
authors.lastname: Vallet
authors.forename: Régis
authors.initials: R
authors.lastname: Bordet
authors.forename: Benoît
authors.initials: B
authors.lastname: Tavernier
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology; D011345:Fenofibrate / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D047493:PPAR alpha / Q000187:drug effects*; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
chemical_list: D004731:Endotoxins; D000960:Hypolipidemic Agents; D008070:Lipopolysaccharides; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; D002118:Calcium; D011345:Fenofibrate