title: Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress.
abstract: BACKGROUND
  Recombinant human activated Protein C (APC) is used as an adjunctive therapeutic treatment in septic shock. APC seemingly acts on coagulation-inflammation interaction but also by decreasing proinflammatory gene activity, thus inhibiting subsequent production of proinflammatory cytokines, NO and NO-induced mediators, reactive oxygen species production and leukocyte-endothelium interaction. The hemodynamic effects of APC on arterial pressure and cardiac function are now well established in animal models. However, the specific effects of APC on heart and vessels have never been studied.
  
  
  OBJECTIVE
  To investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways.
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  University medical center research laboratory.
  
  
  METHODS
  Rats were exposed to lipopolysaccharide (LPS) (10 mg/Kg intravenous). Endotoxic shock was treated with infusion of saline with or without APC (33 microg/kg/h) during 4 hrs. Hemodynamic parameters were continuously assessed and measurements of muscle oxygen partial pressures, NO and superoxide anion (O2(-)) by spin trapping, of NF-kappaB, metalloproteinase-9 (MMP-9) and inducible NO synthase (iNOS) by Western blotting, as well as leukocyte infiltration and MMP-9 activity were performed at both the heart and aorta level (tissue).
  
  
  RESULTS
  APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased up-regulation of NF-kappaB, iNOS and MMP-9. LPS-induced tissue increases in NO and O2(-) production were decreased by APC. Furthermore, APC decreased tissue leukocyte infiltration/activation as assessed by a decrease in myeloperoxidase and matrix metalloproteinase 9 activity.
  
  
  CONCLUSIONS
  These data suggest that APC improves cardiovascular function: 1) by modulating the endotoxin induced-proinflammatory/prooxidant state, 2) by decreasing endothelial/leukocyte interaction and 3) by favoring stabilization of the extracellular matrix.
authors.affiliation: Groupe CHOC, Equipe AVENIR Inserm, Nancy Université, Faculté de Médecine, 54500 Vandoeuvre les Nancy, France.
authors.forename: Nacira
authors.initials: N
authors.lastname: Sennoun
authors.forename: Sennoun
authors.initials: S
authors.lastname: Nacira
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
authors.forename: Olivier
authors.initials: O
authors.lastname: Dessebe
authors.forename: Valérie
authors.initials: V
authors.lastname: Cattan
authors.forename: Solène
authors.initials: S
authors.lastname: Collin
authors.forename: Chantal
authors.initials: C
authors.lastname: Montemont
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gibot
authors.forename: Pierre
authors.initials: P
authors.lastname: Asfar
authors.forename: Andriantsitohaina
authors.initials: A
authors.lastname: Ramaroson
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.forename: Veronique
authors.initials: V
authors.lastname: Regnault
authors.forename: Michel
authors.initials: M
authors.lastname: Slama
authors.forename: Thomas
authors.initials: T
authors.lastname: Lecompte
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Bruno
authors.initials: B
authors.lastname: Levy
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D019446:Endotoxemia / Q000150:complications; D006321:Heart / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011486:Protein C / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated