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

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.

• Authors: A Phillip Owens 3rd, Freda H Passam, Silvio Antoniak, Stephanie M Marshall, Allison L McDaniel, Lawrence Rudel, Julie C Williams, Brian K Hubbard, Julie-Ann Dutton, Jianguo Wang, Peter S Tobias, Linda K Curtiss, Alan Daugherty, Daniel Kirchhofer, James P Luyendyk, Patrick M Moriarty, Shanmugam Nagarajan, Barbara C Furie, Bruce Furie, Douglas G Johns, Ryan E Temel, Nigel Mackman
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 2 Pg. 558-68 (Feb 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22214850 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Lipoproteins, LDL
• Receptors, LDL
• TLR4 protein, human
• TLR6 protein, human
• Toll-Like Receptor 4
• Toll-Like Receptor 6
• oxidized low density lipoprotein
• Thromboplastin
• Simvastatin

Topics

• Animals
• Anticholesteremic Agents (pharmacology)
• Blood Coagulation (drug effects, physiology)
• Cells, Cultured
• Chlorocebus aethiops
• Humans
• Hypercholesterolemia (blood)
• Lipoproteins, LDL (metabolism)
• Male
• Mice
• Monocytes (metabolism)
• Receptors, LDL (genetics, metabolism)
• Simvastatin (pharmacology)
• Thromboplastin (metabolism)
• Thrombosis
• Toll-Like Receptor 4 (genetics, metabolism)
• Toll-Like Receptor 6 (genetics, metabolism)