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

91 Citations (Scopus)

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

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Endotoxins
Saphenous Vein
Blood Vessels
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Chemokine CCL2
Interleukin-8
Atherosclerosis
Prenylation
Toll-Like Receptor 4
Endotoxemia
Fluorescent Dyes
Chemokines
Superoxides
Superoxide Dismutase
Smooth Muscle Myocytes
Monocytes
Cultured Cells
Healthy Volunteers
Oxidoreductases

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Low-level endotoxin induces potent inflammatory activation of human blood vessels : Inhibition by statins. / Rice, James B.; Stoll, Lynn L.; Li, Wei Gen; Denning, Gerene M.; Weydert, Jamie; Charipar, Elizabeth; Richenbacher, Wayne E.; Miller, Francis J.; Weintraub, Neal L.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 23, No. 9, 01.09.2003, p. 1576-1582.

Research output: Contribution to journalArticle

Rice, James B. ; Stoll, Lynn L. ; Li, Wei Gen ; Denning, Gerene M. ; Weydert, Jamie ; Charipar, Elizabeth ; Richenbacher, Wayne E. ; Miller, Francis J. ; Weintraub, Neal L. / Low-level endotoxin induces potent inflammatory activation of human blood vessels : Inhibition by statins. In: Arteriosclerosis, thrombosis, and vascular biology. 2003 ; Vol. 23, No. 9. pp. 1576-1582.
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T1 - Low-level endotoxin induces potent inflammatory activation of human blood vessels

T2 - Inhibition by statins

AU - Rice, James B.

AU - Stoll, Lynn L.

AU - Li, Wei Gen

AU - Denning, Gerene M.

AU - Weydert, Jamie

AU - Charipar, Elizabeth

AU - Richenbacher, Wayne E.

AU - Miller, Francis J.

AU - Weintraub, Neal L.

PY - 2003/9/1

Y1 - 2003/9/1

N2 - 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.

AB - 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.

KW - Atorvastatin

KW - Monocytes

KW - Saphenous veins

KW - Superoxide

KW - Toll-like receptor-4

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