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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1576.)
© 2003 American Heart Association, Inc.

Vascular Biology

Low-Level Endotoxin Induces Potent Inflammatory Activation of Human Blood Vessels

Inhibition by Statins

James B. Rice^*; Lynn L. Stoll^*; Wei-Gen Li; Gerene M. Denning; Jamie Weydert; Elizabeth Charipar; Wayne E. Richenbacher; Francis J. Miller, Jr; Neal L. Weintraub

From the Departments of Internal Medicine (J.B.R., L.L.S., W.-G.L., G.M.D., E.C., 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 (G.M.D., N.L.W.), Iowa City, Iowa.

Correspondence to Dr Lynn L. Stoll, Department of Internal Medicine, Cardiovascular Division, 610 MRC, University of Iowa College of Medicine, Iowa City, IA 52242. 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 protein-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 were 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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