5060Dyslipidemia associated oxidised ldl induces platelet hyperactivity through a cd36-dependent activation of pde3a
Bibliographic record
Abstract
Introduction: Endothelial Prostacyclin (PGI2) prevents excessive platelet activation at sites of vascular injury by elevation of intracellular cyclic adenosine monophosphate (cAMP) and subsequent platelet inhibition. Dyslipidemia is characterized by a prothrombotic phenotype of unknown origin. Here we describe a novel concept between dyslipidemia induced platelet hyperactivity and impaired platelet inhibition by modulated cAMP signalling. Methods: Experimental human and murine platelet function was examined by flow cytometry (BD Fortessa), aggregation (Aggrolink) and in vitro thrombosis assays (Cellix Ltd). Intraplatelet cAMP levels were measured by ELISA (GE Healthcare) while PDE3A activity (Enzo Lifescience) was examined in vitro after immunopreciptation from treated and untreated cells. Results: In patients with stable coronary artery disease (CAD) increased LDL-C levels were associated with reduced platelet sensitivity to endothelial PGI2 (R2=0.224, p=0.003) and reduced inhibitory VASP phosphorylation (low-LDL 622.57±107.96AU; high-LDL 350.64±76.86AU p=0.046). Interestingly, under experimental conditions oxidised LDL (oxLDL), but not native LDL, treated platelets (nLDL) showed a similar effect and reversed the effects of PGI2 in aggregation (p<0.0001) and in-vitro flow (p=0.047). In addition, treatment of platelets with oxLDL, but not nLDL, was associated with decreased PGI2-induced cAMP levels (p=0.0001), which could be corrected by the phosphodiesterase 3A (PDE3A) inhibitor milrinone. Immunoblotting confirmed that oxLDL but not nLDL, induced a dose dependent activatory phosphorylation of PDE3A (serine 428) which was associated with increased PDE3A enzyme activity. For subsequent signaling studies we confirmed, that the effects of oxLDL on PDE3A were mimicked by its structural component the oxidised phospholipid KOdiA-PC, which is specific for the scavenger receptor CD36. Using KOdiA-PC and pharamacological inhibitors we confirmed that PDE3A activation needed sequential activation of Src, Syk and protein kinase C (PKC), and that the signaling events lay downstream of CD36. In a last set of experiments we confirmed that platelets from high-fat diet fed wild-type mice had a reduced sensitivity to the inhibitory effects of PGI2 on aggregation and thrombosis, which was associated with increased plasma levels of oxLDL (p=0.042). Strikingly, PGI2 sensitivity under high-fat conditions was unaltered in CD36-/- platelets. In a model of oxLDL tail vein injections the oxLDL induced platelet hyperactive state was corrected by pretreatment with milrinone confirming the role of PDE3A in vivo.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".