Abstract 10742: Implication of the Importins KPNA2 and KPNB1 in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the elevation of mean pulmonary arterial pressure and resistance, culminating in right ventricular failure and premature death. Pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients exhibit cancer-like phenotypes such as exaggerated proliferation and resistance to apoptosis, key elements contributing to pulmonary arteries (PA) remodeling. Taking benefits of our previously published proteomic study realized on PASMCs isolated from PAH and control patients, we identified the upregulation of importins proteins, namely KPNA2 and KPNB1. The importins contribute to the nucleocytoplasmic shuttling of macromolecules and transcription factors. Cancer studies highlighted the contribution of the KPNA2 and KPNB1 complex in the pro-proliferative and anti-apoptotic phenotypes of cancer cells. Given the cancer-like phenotype of PAH cells, we hypothesized that increased KPNA2-KPNB1 expression promotes PASMCs survival and adverse PA remodeling.We confirmed that KPNA2 and KPNB1 expression is increased in PASMCs and distal PAs isolated from PAH patients compared to controls (western-blot, n=8-9, p<0.05). Similarly, we reported an increased expression of KPNA2-KPNB1 in 3 preclinical models of PH: hypoxic mice, monocrotaline rats and Sugen-hypoxia (Su-Hx) rats (n=8-12, p<0.05). In vitro , molecular (siRNA) and pharmacological (Ivermectin) inhibition of KPNA2-KPNB1 complex decreases PAH-PASMCs proliferation (WB: PCNA; IF: Ki67 and EdU incorporation labeling) and resistance to apoptosis (WB: Survivin; IF: Annexin V labeling) (n=5, p<0.5). Those results are associated with decreased expression of NFAT, NF-kB and STAT3. In vivo , Ivermectin improved PA remodeling (EVG staining) and hemodynamic parameters as assessed by echocardiography (PAAT, TAPSE) and right heart catheterization (RVSP, SV, CO) in Su-Hx rats (n=20, p<0.05). We demonstrated 1) an increased expression of the importins KPNA2 and KPNB1 in PAH, 2) targeting KPNA2-KPNB1 reverses adverse PA remodeling and PH development. Thus, the repurposing of Ivermectin could represent a novel therapeutic strategy from the laboratory bench to patients’ bedside to reverse PAH development.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".