on June 19, 2003
Published online before print June 19, 2003, doi: 10.1161/01.ATV.0000081741.38087.F9
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Submitted on April 9, 2003
Accepted on May 13, 2003
Low-Level Endotoxin Induces Potent Inflammatory Activation of Human Blood Vessels. Inhibition by Statins
James B. Rice ;
From the Departments of Internal Medicine (J.B.R., L.L.S., W.-G.L., G.M.D., F.J.M. Jr, N.L.W.), Biochemistry (W.-G.L.), Pathology (J.W.), and Surgery (W.E.R.), University of Iowa College of Medicine, and the Veteran's Administration Medical Center (E.C.), Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: stolll{at}mail.medicine.uiowa.edu.
Background--Low-level endotoxemia (ie, 
50 pg/mL) in apparently healthy subjects was recently identified as a powerful, independent risk factor for atherosclerosis.
Methods and Results--We treated human saphenous veins (HSVs) with low levels of endotoxin. Release of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant peptide-1 (MCP-1) was measured by ELISA. Superoxide was determined by using the fluorescent probe dihydroethidium (HE), and monocyte binding was assessed with calcein-labeled U-937 cells. Three- to 4-fold increases in MCP-1 and IL-8 release were observed at endotoxin concentrations of 100 pg/mL; these increases were inhibited by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Studies in cultured endothelial cells suggest that the mechanism is related to inhibition of isoprenylation (ie, geranylgeranylation) rather than cholesterol formation. Endotoxin produced dose-dependent increases in HE fluorescence that was inhibited by the superoxide dismutase mimics Tiron and MnTBAP. Endotoxin potently induced U-937 cell binding to HSV; binding was inhibited by both Tiron and atorvastatin. Toll-like receptor-4 expression was detected in cultured HSV endothelial and smooth muscle cells and in intact HSV.
Conclusions--Clinically relevant levels of endotoxin, as reported in ambulatory populations, have profound inflammatory effects on intact HSV. Inhibition of endotoxin-induced vascular inflammation might contribute to the beneficial effects of statins in treating atherosclerosis.
Key words: toll-like receptor-4 • superoxide • monocytes • saphenous veins • atorvastatin
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