Abstract 17701: Nrf2 Inhibits NF-κB Activation During Ischemia Reperfusion Injury and Suppresses Subsequent Development of Cardiac Allograft Vasculopathy in Murine Heart Transplantation
Bibliographic record
Abstract
Introduction: Recent studies suggest that ischemia reperfusion injury (IRI) activates the NF-κB pathway leading to the subsequent development of cardiac allograft vasculopathy (CAV). Nrf2 has been suggested to inhibit NF-κB activation during IRI in other organs; however, the role in myocardial IRI and CAV remains unclear. Therefore, we examined the effects of Nrf2 induction and knockout (KO) on IRI-mediated NF-κB activation as well as CAV using a murine transplant (Tx) model. Methods: Nrf2 wild-type (WT) and KO mice were used as donors, with WTs used as recipients for IRI studies and Bm12 mice for CAV studies. Donor hearts received 2hrs of cold ischemia before Tx. Twenty-five mg/kg sulforaphane (SF, a known Nrf2 agonist) was given to donors 24hrs prior to surgery and to recipients just after Tx to induce Nrf2, with saline as vehicle control (SA). Donor hearts were procured after 24hrs of reperfusion in IRI studies. In CAV studies, recipients received daily 5mg/kg SFN or saline until day 56 when donor hearts were procured (n=6/group). Results: In IRI, NF-κB activity measured by percentage of the cells with nuclear p65 (Figure A) was significantly higher in KO-SA compared with WT-SA (38±4 vs 24±4%, p<0.001). WT-SF displayed notably less NF-κB activity compared with WT-SA (13±5 vs 24±4%, p=0.002). The mRNA levels of NF-κB-mediated inflammatory cytokines were significantly higher in KO-SA compared with WT-SA, and WT-SF displayed lower levels of these mRNA compared with WT-SA (Figure B). In the chronic CAV studies, WT-SA displayed less coronary occlusion area compared with KO-SA (21±8 vs 42±12%, p=0.005). Furthermore, WT-SF showed significantly less coronary occlusion compared with WT-SA (21±8 vs 8±4%, p=0.005) (Figure C). Conclusions: Our results suggest that Nrf2 inhibits NF-κB activation during IRI and suppresses subsequent development of CAV. The Nrf2 pathway may be a promising pharmacological target to prevent development of CAV via its anti-inflammatory properties.
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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) | 0.001 | 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) | 0.006 | 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".