Abstract 240: High-Density Lipoproteins Augment Hypoxia-Induced Angiogenic Regulation via Mediators in the HIF-1α Signaling Pathway
Bibliographic record
Abstract
Background: Angiogenesis plays a critical role in tissue neovascularization in response to ischemia, particularly in collateral vessel development following myocardial infarction (MI). One of the key pathways involved in hypoxia-induced angiogenesis is the HIF-1α/VEGF pathway. High-density lipoproteins (HDL) are associated with improved survival and prognosis following MI, suggesting that it may play a role in hypoxia-induced angiogenic regulation. We assessed the hypothesis that HDL regulates the HIF-1α/VEGF pathway in vitro . Methods: Human coronary artery endothelial cells (HCAECs) were pre-incubated with PBS (control) or reconstituted HDL (rHDL) for 24 hrs then subjected to either normoxic or hypoxic conditions for a further 6 hrs. Protein and gene expression of key mediators in the HIF-1α/VEGF pathway were investigated. Results: As expected, hypoxia elevated HIF-1α protein levels (49%, p<0.05), which was augmented by a further 30% (p<0.05) in rHDL-treated HCAECs. Consistent with this, rHDL increased VEGF mRNA levels above hypoxia-induced increases (23%, p<0.05). Prolyl hydroxylases (PHD 1-3) hydroxylate HIF-1α, targeting it for degradation. rHDL pre-incubation inhibited hypoxia-induced increases in PHD2 and PHD3 levels (32% and 45%, respectively, p<0.05), indicating that rHDL may protect against HIF-1α degradation and explains the rHDL-induced elevation in HIF-1α protein levels. Furthermore, the mRNA levels of Siah-1 and Siah-2, which promote PHD degradation, were increased in rHDL-treated HCAECs (58% and 88% respectively, p<0.05). To determine the importance of Siah-1 and Siah-2 in the HDL-induced modulation of the HIF-1α/VEGF pathway, a siRNA knockdown approach was used. When cells had low levels of Siah-1 and -2, HDL’s ability to induce VEGF was completely attenuated. Conclusion: In conclusion, we found that HDL is able to augment the HIF-1α/VEGF pathway through the stabilization of HIF-1α protein via a decrease in PHD2/3 and increase in Siah1/2. These findings suggest that rHDL may stimulate hypoxia-induced angiogenic regulation via the HIF-1α pathway, which may have implications for preventing ischemic injury following MI.
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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) | 0.007 | 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".