Abstract 240: Inhibition of Glycogen Synthase Kinase 3 Beta Improves EPC Yield, Function and Ameliorates Arterial Repair Post-injury and Stenting
Bibliographic record
Abstract
Endothelial progenitor cells (EPCs) are circulating undifferentiated pluripotent cells capable of reconstituting endothelium in vivo and diminishing lesion formation following arterial injury. We tested the hypothesis that treatment with a specific soluble GSK 3β-inhibitor (GSK3βi) would improve the in vitro yield and function of EPCs from patients with coronary artery disease (CAD) and augment their in vivo potential to improve arterial repair after injury and stent implantation. In vitro treatment with GSK3βi at 1× (IC50) and 2× (IC50) increased the number of cells that dual labelled for acLDL and UEA-1 lectin on day 7 (13.4±3.2 vs. 39.9±5.3 vs. 43.8±10.1; p < 0.05). Furthermore, GSK3βi significantly augmented CAD-EPC survival to levels equal to those of healthy controls, increased VEGF secretion (7.1±1.6 vs 30.0±8.9, p<0.05) and resulted in a 4× increase in adhesion (p<0.05). Using Q-PCR, mRNA copy numbers for VLA-1,2,3,4 and 5 were assayed; however, only VLA-4 levels increased (4×, p<0.01). Use of a VLA-4 specific blocking antibody confirmed that the improved EPC adhesion was specifically mediated by VLA-4. Finally, the effects of GSK 3β inhibition were tested in two in vivo models of arterial injury. CD-1 athymic nude mice underwent femoral artery wire injury and injection of CAD-EPCs that were either GSK3βi treated, untreated, or injection with vehicle alone. GSK3βi treated EPCs improved the ability of xenotransplanted cells to inhibit lesion formation when compared to untreated and vehicle arteries respectively (intima/media ratios: 0.3±0.1 vs. 5.3±1.2 vs 11.2±2.7 μm, p<0.01). GSK3βi coated stents were inserted into rabbit carotid arteries. Fourteen days after stent deployment, GSK3βi stents resulted in a 44% increase in re-endothelialization (assessed by scanning electron microscopy and compared to vehicle coated stents; p<0.01) and a 16% trend towards a reduction in neointima formation (p<0.09). In summary, our data demonstrates that GSK3βi improves EPC function in vitro and ameliorates arterial repair following injury and stent insertion 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) | 0.001 | 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".