Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin
A. Phillip Owens III, … , Ryan E. Temel, Nigel Mackman
A. Phillip Owens III, … , Ryan E. Temel, Nigel Mackman
Published January 3, 2012
Citation Information: J Clin Invest. 2012;122(2):558-568. https://doi.org/10.1172/JCI58969.
View: Text | PDF
Research Article

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 III, 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

×

Figure 6

Hypercholesterolemia increases fibrin deposition and platelet accumulation in a laser-induced cremaster arteriole model of thrombosis.

Options: View larger image (or click on image) Download as PowerPoint
Hypercholesterolemia increases fibrin deposition and platelet accumulati...
Male Ldlr–/– mice fed either chow or HFD for 12 weeks (n = 3 mice per group) underwent cremaster arteriole laser injury (chow, 24 thrombi; HFD, 20 thrombi). (A) Fibrin and (D) platelet deposition were measured by intravital microscopy in which median fluorescent units (MFU) represented as AU were plotted against time for 200 seconds. Representative combined binarized fluorescence and bright field microscopy images of peak fibrin deposition in chow-fed (B) and HFD-fed (C) mice labeled with a fibrin-specific antibody conjugated to Alexa Fluor 647 (red) or peak platelet accumulation in chow-fed (E) and HFD-fed (F) mice labeled with an anti-CD42b antibody conjugated to DyLight 488 (green). *P < 0.05 fibrin HFD versus chow and platelet HFD versus chow. Data analyzed as AUC with a Mann-Whitney rank sum. Original magnification, ×60. Scale bars: 10 μm.