Abstract 15967: Unravelling the Role of Deoxyhypusine Synthase-Mediated Hypusination of eIF5A in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary Arterial Hypertension (PAH) is characterized by progressive distal pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) from PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Appreciation of the pivotal role of translational control in hyperproliferating diseases is steadily increasing. In this regard, eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties. Strikingly, eIF5A is the only protein containing the unique spermidine-derived amino acid hypusine required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased Hyp eIF5A in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and proliferative capacity, leading to pulmonary vascular remodeling. Methods/Results: As assessed by LC-MSMS and WB, expression levels of DHPS, DOHH and both total and hypusinated forms of eIF5A were found increased in PAs and PASMCs from PAH patients and animal models. In vitro , both molecular and pharmacological inhibition of DHPS and DOHH significantly attenuated PAH-PASMCs survival (WB Survivin; Annexin V labeling) and proliferation (WB MCM2, PLK1; Ki67 labeling and EdU incorporation). Hypusine signaling promoted the expression of a broad array of proteins involved in oxidative phosphorylation, supporting the bioenergetic requirements of cell survival and proliferation (LC-MSMS, WB, Seahorse). In vivo , smooth muscle cells-targeted inactivation of one allele of Dhps conferred partial protection against the development of Sugen/Hypoxia (Su/Hx)-induced PAH in mice. Accordingly, pharmacological inhibition of DHPS using GC7 improved hemodynamics (RVSP, mPAP, CO) and vascular remodeling (EVG) in monocrotaline and Su/Hx rats with established PAH. Conclusion: We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".