Abstract Th0017: A Novel Role for Lipoprotein(a) in Potentiating Neutrophil Extracellular Trap Formation
Bibliographic record
Abstract
Introduction: Elevated levels of lipoprotein(a) (Lp(a)) are a risk factor for atherothrombotic events, however the direct contribution of Lp(a) to arterial thrombosis remains unclear. Lp(a) consists of a low-density lipoprotein (LDL)-like moiety linked to apolipoprotein(a) (apo(a)). Lp(a) contains proinflammatory oxidized phospholipids (OxPLs) on apo(a) and on the lipoprotein component of Lp(a), and has potential proinflammatory and prothrombotic properties which are not well understood. NETosis is a form of programmed cell death in which neutrophil extracellular traps (NETs), consisting of exteriorized chromatin, are released in response to inflammation, thereby contributing to immunothrombosis. We hypothesized that Lp(a) can stimulate NETosis; we assessed this by measuring the effect of purified Lp(a) on NETosis using an in vitro assay. Methods: Neutrophils were obtained by differentiation of the HL-60 cells (human promyelocytic leukemia cell line). Neutrophils were treated with phorbol 12-myristate 13-acetate (PMA), a NETosis trigger, in the absence or presence of 250 nmol/L purified Lp(a). NETosis was measured at time points up to 8 hours using a DNA-binding fluorescent dye to measure the extent of chromatin extrusion. Results: A dose-dependent increase in fluorescence was observed, with the greatest NETosis observed between 15.6 nM and 125 nM PMA treatment. We observed that Lp(a) treatment alone did not stimulate NETosis. However, in the differentiated HL-60 cell line, increased NETosis was observed in response to PMA stimulation in the presence of Lp(a), indicating that Lp(a) can potentiate NETosis. Compared to PMA treatment alone, NETosis was initiated earlier and occurs at a higher rate in the presence of Lp(a). Conclusion: We demonstrate, for the first time, that Lp(a) can potentiate NETosis. We predict that this effect may contribute to the prothrombotic effects of Lp(a) in the vasculature through stimulation of coagulation as well as inhibition of fibrinolysis. Future studies will also measure the response of PMA-treated neutrophils to purified apo(a) recombinant apo(a) species either containing or lacking proinflammatory OxPLs. Our findings improve our understanding of the pathogenic mechanisms of Lp(a) and contribute a new perspective to the field through exploration of the possible link between proinflammatory OxPLs on Lp(a) and its potential prothrombotic properties.
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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) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".