Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress.
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.
Sennoun
Nacira
N
Groupe CHOC, Equipe AVENIR Inserm, Nancy Université, Faculté de Médecine, 54500 Vandoeuvre les Nancy, France.
Nacira
Sennoun
S
Meziani
Ferhat
F
Dessebe
Olivier
O
Cattan
Valérie
V
Collin
Solène
S
Montemont
Chantal
C
Gibot
Sebastien
S
Asfar
Pierre
P
Ramaroson
Andriantsitohaina
A
Andriantsitohaina
Ramaroson
R
Regnault
Veronique
V
Slama
Michel
M
Lecompte
Thomas
T
Lacolley
Patrick
P
Levy
Bruno
B
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
D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated