title: Salutary effect of resveratrol on sepsis-induced myocardial depression.
abstract: OBJECTIVE
  We hypothesized that resveratrol administration would reverse sepsis-dependent downregulation of peroxisome proliferator activated receptor-γ coactivator 1α, preserve mitochondrial integrity, and rescue animals from sepsis-induced myocardial failure.
  
  
  METHODS
  Teaching hospital research laboratory.
  
  
  METHODS
  Cecal ligation and puncture in mice was performed to induce sepsis. Mice that underwent cecal ligation and puncture were randomly assigned to receive resveratrol (30 mg/kg or 60 mg/kg) or vehicle 1 mL sodium chloride 0.9% subcutaneously in the scruff of the neck directly after surgery and at 16, 24, and 40 hrs, respectively.
  
  
  RESULTS
  Forty-eight hrs after cecal ligation and puncture, cardiac performance was established using echocardiography. Mitochondrial integrity was evaluated with electron microscopy, and changes in gene expression were evaluated with microarray analysis. Survival at 48 hrs was just under 50% and comparable between groups. Myocardial contractile function significantly improved after resveratrol treatment. Resveratrol-treated mice developed focal areas of edema, whereas vehicle-treated mice developed significant, diffuse myocardial edema. Electron microscopy revealed widespread swollen mitochondria with ruptured outer membranes, autophagosomes, and vacuolation of the internal compartment, which were significantly attenuated in resveratrol-treated animals. Resveratrol treatment significantly increased cardiac expression of peroxisome proliferator-activated receptor-γ coactivator 1a. Microarray analysis revealed that resveratrol treatment resulted in upregulation of the peroxisome proliferator-activated receptor-γ coactivator gene set containing genes known to be regulated by this transcriptional coactivator. Our data strongly suggest that administration of resveratrol modulates bioenergy metabolism, substrate utilization, oxidative stress, and detoxification pathways associated with both mitochondrial and cardiac pathological conditions, but does not alter mortality from sepsis.
  
  
  CONCLUSIONS
  The salutary effects of resveratrol on cecal ligation and puncture-induced myocardial dysfunction are associated with increased peroxisome proliferator-activated receptor-γ coactivator 1a abundance and function. Preservation of myocardial energy production capacity, prevention of secondary injury, mitigation of inflammation, and reversal of sepsis-induced myocardial remodeling are likely to underlie its beneficial effects. This however, does not result in improved survival.
authors.affiliation: Department of Medicine and Interdepartmental Division of Critical Care Medicine, the Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lonneke
authors.initials: L
authors.lastname: Smeding
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Shan
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Haitsma
authors.forename: Eva
authors.initials: E
authors.lastname: Horvath
authors.forename: Suleiman
authors.initials: S
authors.lastname: Furmli
authors.forename: Hussain
authors.initials: H
authors.lastname: Masoom
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Kuiper
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: Frans B
authors.initials: FB
authors.lastname: Plötz
authors.forename: Claudia C
authors.initials: CC
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology; D002432:Cecum; D015536:Down-Regulation / Q000187:drug effects; D004487:Edema / Q000209:etiology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D009200:Myocardial Contraction / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011897:Random Allocation; D000077185:Resveratrol; D018805:Sepsis / Q000150:complications*; D013267:Stilbenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D014665:Vasodilator Agents; D000077185:Resveratrol