Mitochondrial Hsp90 exerts pro‐survival functions in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
RATIONALE Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and no therapeutic option. Although the causal pathomechanisms contributing to remodeling of the pulmonary vascular bed in PAH are still unclear, several features, including hyperproliferation and resistance to apoptosis of pulmonary smooth muscle cells (PASMCs) sustained by oncogenic pathways activation and metabolic alterations, have led to the emergence of the cancer‐like concept. The molecular chaperone heat shock protein 90 (Hsp90), by interacting with its client proteins, is directly associated with malignant growth and proliferation. In addition to be highly expressed in the cytosol, Hsp90 exists in a subcellular pool compartimentalized in the mitochondria (mtHsp90) of tumor cells, but not in normal cells, where it promotes cell survival. OBJECTIVE We hypothesized that Hsp90 up‐regulation in PAH triggers PASMC proliferation and resistance to apoptosis. METHODS AND RESULTS We showed that Hsp90 is up‐regulated in lungs and PASMCs isolated from distal pulmonary arteries from PAH patients compared to control donors. Using pharmacological inhibitors (AT13387 and 17‐AAG), we demonstrated that cytosolic Hsp90 stabilizes the expression of numerous clients proteins overexpressed in PAH that promote cell growth and survival. More importantly, we demonstrated that Hsp90 is specifically expressed in PAH‐PASMCs mitochondria (immunoblot, dual immunofluorescence and immunogold electronic microscopy), and not in healthy cells. Whereas cytosolic Hsp90 inhibition displays a lack of absolute specificity for PAH‐PASMCs, selective inhibition of mtHsp90 activity using Gamitrinib decreased PAH‐PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In PAH‐PASMCs, mtHSP90 accumulation prevents the accumulation of mitochondrial DNA damage and maintains bioenergetics functions (Seahorse). In the fawn‐hooded rat and monocrotaline‐induced models of PAH, mtHsp90 inhibition reduces PA remodeling thus improving pulmonary hemodynamic parameters. CONCLUSION We demonstrated for the first time that accumulation of mtHsp90 is a cardinal feature of PAH‐PASMCs, contributing to the development of vascular lesions. Support or Funding Information ENTELLIGENCE young investigator program
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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".