Abstract 42: Monocyte Tissue Factor-Dependent Activation of Coagulation in Hypercholesterolemic Mice and Monkeys Is Inhibited by Simvastatin
Bibliographic record
Abstract
Hyperlipidemia is associated with a prothrombotic state that includes activation of platelets. However, the molecular pathway that leads to the activation of the coagulation cascade has not been defined. Hyperlipidemia leads to the presence of low levels of oxidized lipoproteins, such as oxidized LDL (oxLDL), in the circulation and the accumulation of oxLDL in atherosclerotic lesions.. Monocytes and macrophages are activated by oxLDL binding to a TLR4/TLR6/CD36 receptor complex. We hypothesized that oxLDL induction of monocyte tissue factor (TF) expression and the release of TF-positive microparticles (MPs) produces a prothrombotic state. In support of this hypothesis, we found that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma MP TF activity. Furthermore, a western 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. Inhibition of TF or a genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity consistent with a role of the TLR4/TLR6/CD36 complex in oxLDL induction of monocyte TF expression. Importantly, simvastatin treatment of hyperlipidemic 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 hyperlipidemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6/CD36 receptor complex. Furthermore, simvastatin appears to act at multiple levels to reduce the prothrombotic state.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".