Abstract 4921: Endothelial-targeted Expression of a Conditional Fas-fKBP Chimera in Transgenic Mice Establishes the Role of Lung Microvascular Apoptosis in Pulmonary Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arteriolar remodeling and obliteration. Although its pathogenesis is still unclear, endothelial cell (EC) apoptosis has been suggested to be an initiating event in PAH, possibly leading directly to the degeneration of fragile precapillary arterioles. This study was to create a transgenic model of tritrable EC apoptosis to test the hypothesis that this is sufficient to induce the PAH phenotype. Methods: The Fas-Induced Apoptosis (FIA) construct contains the Fas cytoplasmic death domain fused with 2 copies of the FK506-binding peptide (FKBP) domain. This construct was targeted to ECs (i.e. EFIA) under the control of the Tie2 promoter and apoptosis was induced by a small molecule dimerizing agent, AP20187, which binds tightly to the FKBP domain. After in vitro validation of its activity, the EFIA gene construct was microinjected into fertilized oocytes in CD1 mice. Apoptosis was assessed by TUNEL staining and right ventricular systolic pressure (RVSP) and hypertrophy (RV/LV+septal weight) were determined with and without i.p. injection of AP20187. Results: EFIA transgenic mice appeared normal, however, administration of the AP20187 at 10 mg/kg/day for 2 weeks resulted in an increase in RVSP, which was greater in homozygous vs. heterozygous EFIA mice (37 ± 7 and 31 ± 7 mm Hg, respectively) compared WT mice either with or without AP20187 (26 ± 2 and 23 ± 2, respectively; p = 0.02). As well, there was a significant increase in right ventricular remodeling in homozygous EFIA mice treated with AP20187 compared to WT mice (RV/LV+ septal wt: 0.366 ±0.132 vs. 0.244 ± 0.048, respectively). AP20187 treatment also induced apoptosis in the peripheral lung (0.22 ± 0.05%) as well as in the kidney (9 ± 2%), which was significantly correlated with increases in RVSP. Of noted, increased lung cell proliferation, as evidenced by PCNA staining, was seen only in AP20187-treated EFIA mice. Conclusions: These results provide the first evidence that EC apoptosis is sufficient to produce PAH. This was characterized in EFIA mice by both increased peripheral lung apoptosis and reactive cellular proliferation, thus representing a new tool to further explore the pathogenesis of the lethal disease.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".