SMAD3 regulation contributes to lung vascular remodeling in pulmonary arterial hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by remodelling of pulmonary arteries, smooth muscle cell hyperplasia and hypertrophy. TGF-β, regulating cell proliferation, migration, and cell death, is elevated in PAH, and has been implicated in its pathogenesis based on clinical and experimental data. TGF-β binding to its receptor activates downstream signalling cascades, such as SMAD proteins. Recent data suggest that SMAD3 is downregulated in PAH. We thus hypothesize that loss of SMAD3 contributes to two major features of PAH: proliferation and hypertrophy (via disinhibition of the myocardin-related transcription factor (MRTF), a myogenic gene inducer). Here, we investigated the regulation of SMAD3 and its interaction with MRTF in human pulmonary arterial smooth muscle cells (PASMC) in vitro and in vivo, and its potential role in PAH. Results: TGF-β treatment for 72 h caused a significant downregulation of SMAD3 mRNA and protein levels in PASMC. Loss of SMAD3 was also evident in pulmonary arteries from rats with monocrotaline-induced PAH. Silencing of SMAD3 in PASMCs increased the proliferative response upon stimulation with fetal calf serum as determined by western blotting for proliferating cell nuclear antigen protein, Ki-67 positive cells, and bromodeoxyuridine assay. Co-immunoprecipitation revealed a reduced interaction between SMAD3 and MRTF in TGF-β treated PASMCs compared to control cells. Conclusion: The present data suggest that SMAD3 downregulation, which occurs in PASMC both in vitro and in vivo, contributes to increased proliferation and - through MRTF liberation - to hypertrophy of PASMC, key features of lung vascular remodeling 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".