Abstract 17233: Clock Modulating Small Molecule SR9011 Enhances Cell Cycle Arrest in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background: Pulmonary arterial hypertension (PAH) is a rapidly progressing disease of the lung vasculature, characterized by the remodeling of small pulmonary arteries in which pulmonary arterial smooth muscle cells (PASMCs) exhibit a cancer-like phenotype, with uncontrolled replication, self-sustaining growth signals, evasion of growth suppressors and resistance to apoptosis. In healthy cells, cell division is controlled by the circadian clock resulting in timed mitosis and rhythmic DNA replication. This suggests that impaired circadian clock might be involved in the cell cycle disorders seen in PAH. Especially, impaired function of the nuclear receptor Rev-Erbα (a core clock protein) has been associated with circadian clock impairment and cell cycle disorders in cancer. Hypothesis: Rev-Erbα impairment is involved in PAH pathogenesis. Methods & Results: We synchronized (Zeitgeber method using 50% horse serum for 2 hours) human PASMCs isolated from 4 PAH patients and 4 controls, and demonstrated a reduced (p=0.0192) (immunoblot) expression of Rev-Erbα 12 hours post synchronization in PAH-PASMCs compared to controls, associated with increased proliferation (Ki67 assay) and resistance to apoptosis (annexin V assay) (p<0.05), which were reversed by the Rev-Erbα agonist SR9011 (10μM for 24h). RNAseq (n=4/group) demonstrated that most of the downregulated (2-fold cut-off) genes following SR9011 treatments were involved in cytokinesis, meiosis, mitotic processes, cell cycle progression, chromosome segregation and recombination (p<0.05). In vivo , Rev-Erbα was also significantly decreased in male and female monocrotaline rats. SR9011 treatments (n=15/group) for 2 weeks (50mg/kg, i.p.) improved PA hemodynamics ( RVSP:47.80mmHg vs 75.29mmHg \mPAP:26.69mmHg vs 44.36mmHg, p<0.0001); vascular remodeling, decreased proliferation(p=0.0001), increased apoptosis(p=0.0002)) and decreased RV hypertrophy (Fulton Index:0.3869 vs 0.5093 p=0.0006) compare to vehicle treated rats. These results were also repeated in the Fawn Hooded rats model. Conclusion: Our results suggest the involvement of Clock pathways in PAH etiology and thus open new avenue of investigation in PAH and new therapeutic options using clock-modulating small molecules.
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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) | 0.005 | 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".