Role for Bromodomain‐Containing Protein 4 in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background Pulmonary arterial hypertension (PAH) is associated with sustained DNA damage accounting for a PARP‐1‐dependent downregulation of miR‐204, promoting the expression of oncogenes (Survivin, Pim‐1). Once activated through the transcription factor NFAT, they contribute to the pro‐proliferative and anti‐apoptotic phenotype of PAH‐pulmonary arterial smooth muscle cells (PAH‐PASMC). In cancer, the epigenetic reader Bromodomain‐containing protein 4 (BRD4) sustains cell proliferation. Interestingly, BRD4 is upregulated by DNA damage and is a predicted target of miR‐204. We hypothesized that the PARP‐1/miR‐204‐dependent upregulation of BRD4 triggers the pro‐proliferative and anti‐apoptotic phenotype seen in PAH‐PASMC. Method/Results BRD4 is upregulated (immunoblot; p<0.01) in distal PAs and PASMC of PAH patients (n=9) compared to control (n=5). This increase is miR‐204 dependent, as miR‐204 upregulation using mimic in PAH‐PASMC decreases BRD4 (p<0.05). BRD4 activation in PAH‐PASMC induces Survivin and Pim‐1 expression (immunoblot; p<0.05), leading to mitochondrial hyperpolarization (TMRM; p<0.05), decreasing mitochondrial respiration (Seahorse XFe 24) and increasing NFAT activation (p<0.05), all of which were reversed upon molecular (siRNA) and pharmacological ((+)JQ1) inhibition of BRD4. BRD4 inhibition reverses PAH‐PASMC proliferation (Ki67; p<0.05) and resistance to apoptosis (TUNEL; p<0.05). In vivo, BRD4 inhibition reverses sugen/hypoxia induced PAH in rats. Conclusion Through a miR‐204‐dependent mechanism, BRD4 upregulation triggers the expression of oncogenes contributing to the proliferative and anti‐apoptotic phenotype seen in PAH‐PASMC, whereas BRD4 inhibition improves 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) | 0.002 | 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".