Abstract 445: Beraprost, a Prostacyclin Analogue, Inhibits Human Vascular Smooth Muscle Cell Migration via Activation of Exchange Protein Activated by cAMP (Epac)
Bibliographic record
Abstract
Following vein grafting, endothelial damage initiates vascular smooth muscle cell (VSMC) migration to the intima leading to neointimal hyperplasia and restenosis. Inhibition of VSMC migration is therefore a therapeutic target to prevent restenosis. Previous studies have shown that cyclic adenosine monophosphate (cAMP) inhibits VSMC migration although the downstream mediators are unknown. This suggests that cyclic AMP-producing agonists, such as the prostacyclin analogue beraprost which binds to prostanoid receptors, could be used as a potential drug against neointimal formation. We hypothesised that prostacyclin analogues inhibit VSMC migration by activating specific cAMP downstream mediators. The aims of this project were to examine the role of cAMP mediators protein kinase A (PKA) and Exchange protein activated by cAMP (Epac) in this inhibitory effect. Saphenous veins were obtained from patients undergoing coronary artery bypass. VSMCs were primary cultured and migration measured using a chemotaxis chamber. Cell migration stimulated by PDGF was significantly inhibited by 68 ± 5% (n=6) in the presence of a therapeutically relevant concentration of beraprost (1 nM). To examine potential mechanisms of this inhibition, selective activators of PKA and Epac were used. Both Epac and PKA activators significantly inhibited migration towards PDGF. However, fluorescence resonance energy transfer using cells transfected with specific probes revealed that 1 nM beraprost only activates Epac and not PKA in VSMCs (n=4). The downstream mechanisms were further investigated. Pulldown assays demonstrated that beraprost-mediated stimulation of Epac produces subsequent activation of the monomeric G-protein Rap1 and ultimately inhibits RhoA-induced cytoskeleton rearrangement required for migration (n=3). Using siRNA to knockdown Rap1, the inhibition of PDGF-induced migration by beraprost in VSMC cells was shown to be dependent on the Rap1 pathway (n=3). In conclusion, the prostacyclin analogue beraprost inhibits VSMC migration via activation of Epac/Rap1. This may provide a new therapeutic target to prevent neointimal hyperplasia.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 0.000 |
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 teacher head, 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".