Abstract 10231: Parp1-Pkm2 Axis Mediates Right Ventricular Failure Associated with Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV). Methods and Results: We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI>2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding). In vitro , we confirmed that oxidative DNA damage (ET-1+H 2 O 2 ) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal Parp1 deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H 2 O 2 ). In vivo , Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global Parp1 loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p<0.05) Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".