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Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.

Authors
  • Owens, A Phillip 3rd
  • Passam, Freda H
  • Antoniak, Silvio
  • Marshall, Stephanie M
  • McDaniel, Allison L
  • Rudel, Lawrence
  • Williams, Julie C
  • Hubbard, Brian K
  • Dutton, Julie-Ann
  • Wang, Jianguo
  • Tobias, Peter S
  • Curtiss, Linda K
  • Daugherty, Alan
  • Kirchhofer, Daniel
  • Luyendyk, James P
  • Moriarty, Patrick M
  • Nagarajan, Shanmugam
  • Furie, Barbara C
  • Furie, Bruce
  • Johns, Douglas G
  • And 2 more
Type
Published Article
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Publication Date
Feb 01, 2012
Volume
122
Issue
2
Pages
558–568
Identifiers
DOI: 10.1172/JCI58969
PMID: 22214850
Source
Medline
License
Unknown

Abstract

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.

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