Abstract 17076: Attenuating Endoplasmic Reticulum (ER) Stress as a Novel Therapeutic Strategy in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
The poor prognosis associated with pulmonary arterial hypertension (PAH) is in part, due to the complex and poorly understood pathogenesis. ER stress is a potential common denominator among many of the seemingly unrelated molecular triggers of PAH, including BMPRII mutations and the misfolded protein response that follows, viruses, inflammation, Notch signaling and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing exchange of Ca2+, lipids and ATP between the organelles. Recently, we showed that disruption of the ER-mito unit was critical in PAH pathogenesis. ER stress-regulated induction of the reticulon protein Nogo caused structural/functional disruption of the ER-mito unit resulting in PAH. Chemical chaperones including the clinically studied 4-phenylbutyrate (PBA) can attenuate ER-stress and have been used in animals and patients to treat metabolic diseases and cancer. We hypothesized that attenuation of ER stress with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. We used two models of PAH associated with ER stress: hypoxia and monocrotaline (MCT). Mice exposed to chronic hypoxia and treated with PBA in the drinking water (~750mg/kg/day) in both prevention and reversal protocols had less distal pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity (see table; data presented as mean±SEM). MCT-animals responded similarly. Mechanistic studies were performed in human cell lines and tissues from these animals. We showed that 2mM PBA decreased ER stress (decrease in the marker grp78), decreased Nogo and normalized the ER-mito unit (mitochondrial calcium and membrane potential). Both in vivo and in vitro, PBA suppressed proliferation (Ki67/PCNA) and induced apoptosis (TUNEL) in SMA+ cells. Metabolism and ER stress may be a common downstream effect of many diverse triggers of PAH and may expose a new therapeutic window.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".