Abstract 2618: Bone Morphogenic Protein-9 Stimulates Endothelin-1 Synthesis by Human Pulmonary Microvascular Endothelial Cells: A Possible Contributor to the Pathogenesis of Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is thought to be related to progressive obliteration of the pulmonary microvasculature. Endothelial proliferation and dysfunction is a central process, and increased levels of the potent endothelial-derived vasoconstrictor and mitogen, endothelin-1 (ET-1) have been described. It is not known what triggers these increased ET-1 levels. With the description of mutations in receptors for bone morphogenic proteins (BMP) and other members of the TGF-beta family of proteins as causative events in hereditary forms of PAH, we hypothesized that BMPs might modulate ET-1 synthesis. Recently, BMP-9, which acts via the type-1 TGF-beta receptor activin-like kinase 1 (ALK-1), has been identified as a potent regulator of endothelial proliferation and migration. We therefore studied the effects of BMP-9 on ET-1 in-vitro production by human lung microvascular endothelial cells (HLMVEC), the cell implicated in the pathogenesis of PAH. HLMVEC were cultured to confluence in EGM-2MV medium and then BMP-9 (0 –100 ng/ml) was added to the medium for 24 and 48 hours. All concentrations increased ET-1 production at both time points, with 10 ng/ml resulting in a 99% increase versus controls at 24 hours and 104% at 48 hours (all p<0.001). Addition of SB-431542 (10 uM) a specific inhibitor of the kinase activity of ALK-5 significantly reduced the 48 hour ET-1 synthesis provoked by BMP-9, with a 41% decrease for 1 ng/ml BMP-9 but only a 9% reduction for 10 and 100ng/ml BMP-9. In conclusion, this is the first identification of BMP-9 as a potent stimulator of ET-1 production by HLMVEC. Although the actions of BMP-9 are thought to be through ALK-1, there may be a component of interaction with ALK-5, or ALK-5 may have cross-talk with ALK-1. ALK-5 inhibitors such as SB-431542 can reduce BMP-9 mediated ET-1 production and might ultimately have therapeutic benefit for PAH.
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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".