Abstract 734: NF-kB Signaling Regulates Mitochondrial Permeability Transition Pore Opening of Cardiac Myocytes via Cyclophilin D (CypD) Modulation
Bibliographic record
Abstract
Nuclear Factor-κB (NF-κB) is ubiquitously present transcription factor that regulates a variety of cellular functions including cell survival. Herein, we show a critical role for NF-κB signaling in regulation of mitochondrial permeability transition pore opening (mPTP) of cardiac myocytes that involves cyclophilin D (CypD). Cardiac myocytes expressing a kinase defective form of IKKβ (IKK K-M ), the principle IKK required for NF-κB activation, displayed impaired NF-κB gene activity. Defects in NF-κB signaling coincided with an increase in mPTP opening and cell death. Interestingly, mPTP opening and cell death observed in the NF-κB defective cardiomyocytes was supressed by inhibition of mPTP modulator CypD, with cyclosporin A (CSA) or by siRNA knock down (CypDsiRNA), suggesting a link between mPTP regulation and NF-κB signaling. Earlier, we reported that doxorubicin (Dox) treatment resulted in severe ultra-structural defects including disrupted mitochondrial cristae and impaired respiration, increased mitochondrial calcium overload, mPTP opening and a widespread cell death. Interestingly, we observed a dramatic reduction in NF-κB signaling in cardiac myocytes treated with doxorubicin (18 Hrs), coupled with mitochondrial dysfunction including impaired respiration. Inhibition of CyPD suppressed doxorubicin induced cell death of cardiac myocytes. Finally restoration of NF-κB signaling in cardiac myocytes treated with doxorubicin by IKKβ, active kinase, suppressed mitochondrial calcium overload, mitochondrial perturbations, respiration and cell death. The data herein, provides the first direct evidence that impaired NF-κB signaling predispose Dox treated cardiac myocytes to cell death. Hence, interventions that preserve NF-κB survival signaling pathways in the heart may prove beneficial in reducing cardiac dysfunction and heart failure in cancer patients undergoing doxorubicin chemotherapy.
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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 | 0.001 | 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 | 0.000 |
| 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".