Abstract P044: Activation of Interferon Regulatory Factor-3 Prolongs Stress-Induced Cardiomyocyte Apoptosis and Decreases Survival Post Myocardial Infarction
Bibliographic record
Abstract
Background. The innate immune response is critical in mediating host protection from foreign antigen or stress. It is evident that multiple innate immune pathways also tightly regulate the remodeling process post-myocardial infarction (MI), however it is not clear how this process is mediated. In order to further elucidate the underlying mechanism of this process, we screened both mouse and human post-MI microarray databases and identified a common, significantly upregulated transcription factor of interest, interferon regulatory factor-3 (IRF3). To assess its function in vivo, we tested the hypothesis that activation of IRF3 post-MI coordinates maladaptive repair by promoting cardiomyocyte apoptosis. Methods/Results. We randomly allocated IRF-3 knockout (IRF-3-/-) mice and their wild-type (WT) counterparts to either left anterior descending (LAD) coronary artery ligation or sham operation. Four weeks post-MI, deficiency in IRF3 led to improved survival [88% (44/50) vs. 29% (14/49) in WT, p<0.0001], preserved cardiac function via echocardiography [Fractional Shortening: 37% vs. 22.9% in WT, LVEDD: 5.15mm vs. 5.85mm in WT, LVESD: 4.15mm vs. 5.14mm in WT; p<0.057#x005D;, and attenuated infarct size [27% vs. 44% in WT, p<0.05]. Assessing the stress response 1-week post-MI, we found that NFkB signaling (IKKa, Ikba, p65) as well as pan-ubiquitination of proteins, were both significantly downregulated in the border infarct zone of IRF3-/- mice. These findings were complemented with increased protein and mRNA expression of de-ubiquitinating enzyme A20. Interestingly, in IRF3-/- mice these results were linked with decreased apoptosis (Caspases, TUNEL staining), however with a more specific attenuation of the mitochondrial-specific apoptotic pathway (Bid, Cytochrome C, Caspase9). Conclusions. These data establish a novel link between the innate immune transcription factor IRF3 and maladaptive regulation of cardiomyocyte apoptosis through mitochondrial apoptotic pathway activation. As an acute responder coordinating maladaptive remodeling, IRF3 may prove to be an efficacious therapeutic target to improve outcome following MI.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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".