Related Experiment Video
Updated: May 26, 2026
Quantification of Monocyte Transmigration and Foam Cell Formation from Individuals with Chronic Inflammatory Conditions
Published on: October 17, 2017
Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by
A Phillip Owens1, Freda H Passam, Silvio Antoniak
1Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Insights
High cholesterol promotes blood clots by increasing oxidized LDL, which triggers tissue factor expression in monocytes via TLR4/TLR6. Simvastatin reduced this prothrombotic state in animal models.
Area of Science:
- Cardiovascular Biology
- Immunology
- Lipid Metabolism
Background:
- Hypercholesterolemia is a key risk factor for atherosclerosis and cardiovascular disease.
- The mechanisms linking hypercholesterolemia to a procoagulant state are not fully understood.
- Oxidized lipoproteins (oxLDL) are implicated in atherosclerosis and may contribute to hypercoagulability.
Purpose of the Study:
- To investigate if hypercholesterolemia elevates plasma oxLDL levels.
- To determine if oxLDL induces tissue factor (TF) expression in monocytes.
- To elucidate the role of oxLDL-induced TF in the prothrombotic state of hypercholesterolemia.
Main Methods:
- In vitro studies using human monocytic cells and monocytes exposed to oxLDL.
- Analysis of plasma microparticle (MP) TF activity in patients with familial hypercholesterolemia and in animal models (LDL receptor-deficient mice, African green monkeys) on a high-fat diet.
- Assessment of coagulation activation and inflammatory markers.
- Studies using genetic deficiency models (TF, TLR4, TLR6) and simvastatin treatment.
Main Results:
- Oxidized LDL (oxLDL) induced tissue factor (TF) expression in human monocytes.
- Patients with familial hypercholesterolemia and hypercholesterolemic animal models exhibited elevated plasma MP TF activity.
- TF deficiency in bone marrow cells reduced coagulation in hypercholesterolemic mice.
- TLR4 or TLR6 deficiency reduced MP TF activity.
- Simvastatin treatment decreased oxLDL, monocyte TF expression, MP TF activity, coagulation, and inflammation in animal models.
Conclusions:
- Hypercholesterolemia induces a prothrombotic state through oxLDL-mediated TF expression in monocytes.
- This process involves the engagement of a Toll-like receptor 4/Toll-like receptor 6 (TLR4/TLR6) complex.
- Targeting oxLDL or TLR signaling may offer therapeutic strategies for hypercholesterolemia-associated thrombosis.
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.
Related Concept Videos
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents