Implication of the transcription Factor FOXM1 in pulmonary arterial hypertension
Bibliographic record
Abstract
RATIONALE Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance, leading to right heart failure and premature death. PAH is characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis within pulmonary artery (PA) wall. Targeting the cancer‐like of PASMCs represents an attractive therapeutic avenue to tackle PAH. Overexpression of the transcription factor FOXM1 has been shown to be a key driver of cancer progression through the stimulation of DNA repair, cell proliferation and cell survival. OBJECTIVE Using a multidisciplinary and translational approach we aimed to demonstrate that up‐regulation of FOXM1 in PAH‐PASMCs triggers proliferation and resistance to apoptosis. METHODS AND RESULTS FOXM1 is significantly increased (immunoblot and immunofluorescence) in lungs, distal PAs, and isolated PASMCs from PAH patients as well as in the monocrotaline (MCT)‐induced PAH model compared to controls. We demonstrated that, in response to growth factors like PDGF and IGF1, Akt is activated (increased P‐Akt), phosphorylates FOXO3a and inhibits it, allowing the up‐regulation of FOXM1. Moreover, we found that inhibition of FOXM1 in PAH‐PASMCs increases DNA damage (gH2AX) and reduces expression of NBS1 and PLK1 (immunoblot), two factors up‐regulated in PAH‐PASMCs (immunoblot and immunofluorescence) and involved in DNA repair and cell cycle progression. Consistently, pharmacological inhibition of FOXM1 using Thiostrepton dose‐dependently reduces PAH‐PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) in vitro . Inhibition of FOXM1 with Thiostrepton improves established PAH (right heart catheterization) in the MCT model. CONCLUSION We showed for the first time that FOXM1 is overexpressed in human PAH and implicated in the pro‐proliferative and anti‐apoptotic phenotype of PAH‐PASMCs. Support or Funding Information None
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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) | 0.001 | 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 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".