Abstract 19761: P27 Inhibits IkBa-Degradation, Attenuates Inflammation, Improves Cardiac Function and Increases Survival Following LPS
Bibliographic record
Abstract
Background : A previous cardiac protein interaction screen suggested that cell cycle inhibitor p27 interacts with IKKα, a kinase that regulates phosphorylation-dependent degradation of IκBα, the inhibitor of NF-κB. Bacterial toxin LPS promotes NF-κB-induced myocarditis. Here we test if p27 can interfere with LPS-induced cardiac dysfunction in vivo . Methods : At 1 and 6 h post-LPS (30 mg/kg i.p.), an HA-tagged TAT-conjugated p27 fusion protein (TAT.p27), a TAT.lacZ control or an equal volume of saline was delivered (20 mg/kg i.p.) to 8-wk old C57BL6 mice. This dose of TAT.p27 was shown capable of entering the heart and increasing total cardiac p27 levels as determined by immunofluorescence for HA-tag and Western blot (WB) for p27. Cardiac structure and function were assessed by 2D-echo and pressure-volume catheters. WBs of heart homogenates for cleaved caspase-3 and Bcl-2, as well as IκBα, were used to assess apoptosis and IκBα turnover. Expression of inflammatory cytokines IL-1β and IL-6 was measured by RT-PCR. Survival was analyzed by Kaplan-Meier plots. Results : Delivery of TAT.p27 at 1 h post-LPS preserved myocardial levels of IκBα at 1.5, 2 and 4 h post-LPS. Co-immunoprecipitation experiments in intact heart showed an interaction between p27 and IκBα. Delivery of TAT.p27 at 6 h post-LPS resulted in improvements vs. saline and TAT.lacZ controls in fractional shortening (%: 38.2±1.2 vs. 29.1±1.5, P<0.01; vs. 27.3±1.8, P<0.001), cardiac output (µl/min: 17332±4619 vs. 12279± 5304, p<0.05; vs. 12959±3221; p<0.01), stroke volume (µl: 28±7 vs. 21±8, p<0.01; vs. 20±5 µl, p<0.05) and stroke work (mJ: 2121±909 vs. 1472±721, p<0.05; vs. 1366±522, p<0.05). For each above result, N≥13 per group. Apoptosis was significantly decreased in TAT.p27-treated mice subjected to LPS, as were mRNA levels of IL-1β and IL-6 as compared to controls. Importantly, these improvements were associated with better survival in TAT.p27-treated mice vs . saline- and TAT.lacZ-treated controls. Conclusion : These data suggest that the p27-IκBα and or IKKα interactions, possibly by preserving cardiac IκBα levels and preventing NFκB activation post-LPS, attenuate inflammation, limit cardiomyocyte apoptosis, and improve survival in a model of endotoxin-induced cardiac dysfunction.
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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 | 0.001 |
| 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".