Nuclear Factor-κB Represses Hypoxia-Induced Mitochondrial Defects and Cell Death of Ventricular Myocytes
Bibliographic record
Abstract
BACKGROUND: Oxygen deprivation for prolonged periods of time provokes cardiac cell death and ventricular dysfunction. Preventing inappropriate cardiac cell death in patients with ischemic heart disease would be of significant therapeutic value as a means to improve ventricular performance. In the present study, we wished to ascertain whether activation of the cellular factor nuclear factor (NF)-kappaB suppresses mitochondrial defects and cell death of ventricular myocytes during hypoxic injury. METHODS AND RESULTS: In contrast to normoxic control cells, ventricular myocytes subjected to hypoxia displayed a 9.1-fold increase (P<0.05) in cell death, as determined by Hoechst 33258 nuclear staining and vital dyes. Mitochondrial defects consistent with permeability transition pore opening, loss of mitochondrial membrane potential (DeltaPsim), and Smac release were observed in cells subjected to hypoxia. An increase in postmitochondrial caspase 9 and caspase 3 activity was observed in hypoxic myocytes. Adenovirus-mediated delivery of wild-type IKKbeta (IKKbetawt) resulted in a significant increase in NF-kappaB-dependent DNA binding and gene transcription in ventricular myocytes. Interestingly, subcellular fractionation of myocytes revealed that the p65 subunit of NF-kappaB was localized to mitochondria. Hypoxia-induced mitochondrial defects and cell death were suppressed in cells expressing IKKbetawt but not in cells expressing the kinase-defective IKKbeta mutant. CONCLUSIONS: To the best of our knowledge, the data provide the first direct evidence that activation of the NF-kappaB signaling pathways is sufficient to suppress cell death of ventricular myocytes during hypoxia. Moreover, our data further suggest that NF-kappaB averts cell death through a mechanism that prevents perturbations to the mitochondrion during hypoxic injury.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".