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 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 | 0.001 |
| 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 | 0.002 |
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".