The Chaperone Protein Hsp90 is Upregulated in Human Pulmonary Hypertension
Bibliographic record
Abstract
INTRODUCTION Human and animal pulmonary arterial hypertension (PAH) is characterized by a selective activation of several transcription factors including STAT3, NFAT and HIF‐1α, which regulates pulmonary artery smooth muscle cells (PASMC) proliferation and apoptosis. The activation mechanisms of these factors in PAH remain elusive. Hsp90 is a major molecular chaperone that is plays a pivotal role in assisting correct folding and functionality of its client proteins. The Hsp90 client proteins include a wide variety of transcription factors like NFAT, STAT3 and HIF‐1α. Recent evidences have shown that miR‐223 may regulates HsP90 expression in cancer, which share many similarities with PAH. We thus hypothesized that the miR‐223/Hsp90 axis is aberrantly expressed in PAH patients, contributing to PAH‐PASMC phenotype. METHODS and RESULTS Using immunoblot, we showed that Hsp90 is upregulated in lungs, and PASMC of PAH patients compared to non‐PAH donors. This upregulation in Hsp90 is associated with a significant downregulation of miR223 in PAH; upregulation of HIF‐1α, NFAT and STAT3 activation measured by immunoblot and nuclear translocation assay. In primary cultured PASMC from 3 PAH and 3 control patients, we demonstrated that miR‐223 upregulation using mimic or Hsp90 molecular inhibition using siRNAs significantly reduces PAH‐PASMC proliferation and resistance to apoptosis. Finally, using monocrotaline‐induced PAH, we showed that miR223 nebulization decreases total pulmonary resistance by decreasing distal PA wall thickness. CONCLUSION The miR223/Hsp90 may represent a new signal hub in PAH, accounting for the activation of several transcription factors contributing to PAH‐PASMC phenotype and thus vascular remolding seen in 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 | 0.000 |
| 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".