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, Neal L. Weintraub

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

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, gerlanylgeranylation) 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.

Original languageEnglish (US)
Pages (from-to)1576-1582
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

Keywords

  • Atorvastatin
  • Monocytes
  • Saphenous veins
  • Superoxide
  • Toll-like receptor-4

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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