Simvastatin blunts endotoxin-induced tissue factor in vivo.
BACKGROUND
Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo.


RESULTS
In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1+2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L.


CONCLUSIONS
Simvastatin suppresses the inflammatory response to endotoxin and blunts monocyte TF expression but does not affect platelet activation.
Steiner
Sabine
S
Second Department of Medicine, Division of Angiology, Medical University of Vienna,Vienna, Austria.
Speidl
Walter S
WS
Pleiner
Johannes
J
Seidinger
Daniela
D
Zorn
Gerlinde
G
Kaun
Christoph
C
Wojta
Johann
J
Huber
Kurt
K
Minar
Erich
E
Wolzt
Michael
M
Kopp
Christoph W
CW
D000328:Adult; D015415:Biomarkers / Q000097:blood; D004731:Endotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D015539:Platelet Activation / Q000187:drug effects; D011292:Premedication; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D019851:Thrombophilia / Q000139:chemically induced / Q000188:drug therapy; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000235:genetics*
D015415:Biomarkers; D004731:Endotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013925:Thromboplastin; D019821:Simvastatin