Low-level endotoxin induces potent inflammatory activation of human blood vessels: inhibition by statins.

Published

Journal Article

BACKGROUND: Low-level endotoxemia (ie, >or=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.

Full Text

Duke Authors

Cited Authors

  • Rice, JB; Stoll, LL; Li, W-G; Denning, GM; Weydert, J; Charipar, E; Richenbacher, WE; Miller, FJ; Weintraub, NL

Published Date

  • September 1, 2003

Published In

Volume / Issue

  • 23 / 9

Start / End Page

  • 1576 - 1582

PubMed ID

  • 12816876

Pubmed Central ID

  • 12816876

Electronic International Standard Serial Number (EISSN)

  • 1524-4636

Digital Object Identifier (DOI)

  • 10.1161/01.ATV.0000081741.38087.F9

Language

  • eng

Conference Location

  • United States