3133Hyperlipidaemia associated oxidised phospholipids induce sustained platelet hyperactivity by CD36 and PLC gamma 2 dependent ROS production
Bibliographic record
Abstract
Introduction: Hyperlipidaemia associated platelet hyperactivity is proposed to play a key role in atherothrombosis. Oxidised LDL (oxLDL) and associated oxidised phospholipids (oxPCCD36) have emerged as a potential causative factor of platelet hyperactivity. Here we identify intracellular reactive oxygen species (ROS) as important driver of platelet hyperactivity and link it to the presence of CD36 and PLCg2. Methods: All experiments were performed on human and murine platelets (WT, CD36−/−, PLCg2−/−). ROS production was measured by fluorescence microscopy under arterial shear or static conditions. P-selectin expression was examined by flow cytometry. Results: Stimulation of human and murine platelets led to the sustained generation of intracellular ROS in response to oxLDL. The synthesis of ROS was mimicked by the oxLDL-associated oxidised phospholipid oxPCCD36 (p<0.001), but lost in CD36 deficient platelets confirming the key role of this receptor (p=0.36). Previously we found that PLCg2 is activated by CD36 ligation but its functional relevance remained elusive. Using PLCg2−/− platelets, we found that ROS production was blunted under static and flow conditions indicating a key role for the lipase (p=0.12). Next we examined the relevance of ROS production on platelet activation by the modified lipoprotein. OxLDL and oxPCD36 induced a time-dependent increase in P-selectin expression that was linked to intracellular ROS generation (oxLDL p<0.001, oxPCCD36 p=0.015). To clarify role and source of ROS we pretreated platelets with the NOX-1 inhibitor ML171, NOX-2 inhibitor gp91ds-tat and the general ROS scavenger N-acetyl-cysteine (NAC). Strikingly, we observed that pharmacological inhibition with the NOX-2 inhibitor and NAC lead to a significantly blunted P-selectin expression (ML171: p=0.865; gp91ds-tat: p=0.027; NAC: 0.035).
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".