Abstract 17066: A Metabolic Basis for Histone Acetylation and a Potential Mechanism of Epigenetic Regulation in Right Ventricular Failure
Bibliographic record
Abstract
Right ventricular (RV) failure is the most critical determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). There is an increasing awareness of important differences between the left ventricle (LV) and RV. Recently, histone deacetylase (HDAC) inhibitors, which increase histone acetylation, have had promising results on maladaptive LV hypertrophy. However, in RV hypertrophy (RVH), HDAC inhibition resulted in RV failure. Recently, nuclear acetylation processes have been shown to be dependent, in part, on the mitochondria. Since there is evidence of mitochondrial diversity between the RV and LV, we hypothesized that histone acetylation may have a metabolic basis and explain the transition to RV failure. In order to study histone acetylation and its relation to metabolism and disease progression in the failing RV, we used a rat model of monocrotaline (MCT)-induced PAH, in which we studied animals with normal RV function (n=6, RVSP=38±2 mmHg, CO=102±2 ml/min and RV/LV+Septum=22±1), compensated RVH (CRV; n=10, RVSP=66±8 mmHg, CO=80±13 ml/min and RV/LV+Septum=48±3, 2-3 weeks post-MCT) and decompensated RVH (DRV; n=9, RVSP=52±2 mmHg, CO=67±10 ml/min and RV/LV+Septum =58±2, 4-6 weeks post MCT). Compared to control, the myocardium (RV free wall) from CRV animals exhibited decreased mitochondrial activity shown by increased mitochondrial membrane potential and decreased mitochondrial-derived reactive oxygen species (mROS). This was associated with increased RV glucose uptake measured by PET in vivo, suggesting a shift of metabolism away from mitochondria towards glycolysis. CRV animals also showed decreased histone-3 (H3) acetylation (IHC/immunoblot). In contrast, DRV animals showed decreased RV glucose uptake, increased mROS as well as induction of the mitochondrial uncoupling-protein 2 in DRV myocardium. These metabolic/mitochondrial changes were associated with an increase in H3 acetylation in the DRV compared to the CRV animals. We show that metabolism and H3 acetylation closely follow mitochondrial remodeling and that these changes separate CRV from DRV potentially opening a new window in our understanding of RV failure.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.004 | 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".