Abstract 211: Targeting the Mitochondrial Fission Protein Dynamin Related Protein 1 to Mitigate Oxygen Toxicity Following Cardiac Arrest
Bibliographic record
Abstract
Introduction: Oxygen administration following cardiac arrest (CA) is associated with cardiac dysfunction, brain injury, and poor survival. These injuries are driven in part by mitochondrial injury, but the specific mechanisms underlying oxygen-induced mitochondrial injury are unclear. Here we hypothesized that oxygen-mediated injury following CA is influenced by the mitochondrial fission protein Dynamin Related Protein 1 (Drp1) and that targeting Drp1 could mitigate the effects of post-CA oxygen toxicity. Methods and Results: Mice underwent brief asystole CA (12 min) followed by cardiopulmonary resuscitation (CPR). One hour following successful CPR, mice were randomized to receive hyperoxia (33% O 2 ), normoxia (21% O 2 ), or hypoxia (10% O 2 ) in an environmental chamber for 6 hours. After exposure, the mice were returned to room air. Hyperoxia and normoxia groups exhibited lower 10-day survival rate compared to mice exposed to hypoxia (15% and 67% vs. 92%, n=13/group, P<0.05, respectively). The hyperoxia group also showed decreased myocardial fractional shortening (30.1±3.0% vs 45.0±1.4%) and neurological scores (5.8±0.8 vs 9.8±0.3) 48 hours post CA compared to the hypoxia group (n=13, P<0.05, respectively). Hyperoxia increased the expression of the activated form of Drp1 (Drp1-S616) to 134% in the heart (n=4, P<0.05) and decreased cardiomyocyte mitochondrial size to 75% (n=30, P<0.05) compared to hypoxia-treated CA mice. The hypoxia-dependent decrease in Drp1 activity was associated with a 46% increase in myocardial mitochondrial respiration (n=5, P<0.01) and a 32% reduction in ROS production vs hyperoxia-treated CA mice (n=6, P<0.05). Administration of the Drp1 GTPase inhibitor Drpitor1a to hyperoxia-exposed post-CA mice increased survival (40% vs 20%), myocardial function (31.5±4.4% vs 42.0±1.3%) and neurological scores (4.1±0.7 vs 9.0±0.0) compared to untreated hyperoxia-exposed post-CA mice (n=10, P<0.05, respectively). Conclusions: Oxygen dependent post-CA injury is partly dependent on the mitochondrial fission factor Drp1. Targeting Drp1 is a promising strategy to limit post-CA oxygen toxicity.
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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 | 0.001 |
| 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".