Abstract 13519: Signaling via PI3Kβ and PI3Kγ and Increased Glucose Oxidation Contribute to the Marked Protection Against Ischemia/Reperfusion Injury in PI3KαDN Hearts
Bibliographic record
Abstract
Introduction: The phosphatidylinositol 3-kinase (PI3K)γ isoform is an important mediator of signals from ligands such as adenosine, which cause protection against ischemia reperfusion (IR) injury. The class 1 PI3K isoforms primarily expressed in the heart are α, β and γ. Reduced PI3Kα signaling in the heart resulted in dramatic protection from IR injury. Here we test the hypothesis that the IR protection with reduced PI3Kα signaling is the result of increased PI3Kγ activation. Methods: PI3Kα dominant negative (DN) mice were crossed with PI3Kγ-/- to create a PI3K double mutant (DM). Also, PI3K DM and PI3Kα DN hearts were perfused with the PI3Kβ selective inhibitor TGX-221 (500 nM). Langendorff perfused hearts were treated with 30 minutes ischemia, and functional recovery was assessed upon 40 minutes of reperfusion. Signaling via Akt and GSK3β pathways was assessed by Western blot. To assess metabolic profile, PI3Kα DN hearts were perfused in the working heart mode with radio labeled substrates for glycolysis and glucose oxidation. Results: PI3K DM hearts showed improved recovery from IR compared to wildtype (wt) hearts: heart rate pressure product (RPP) recovery was 81.4±10.1% and 37.9±2.8%, and LV developed pressure (LVDP) recovery was 98.7±8.4% and 49.6±3.6 (n=6-9) respectively. IR recovery was reduced (RPP: 37.1±6.4%, LVDP: 47.5±7.9% recovery (n=8)) upon pharmacological inhibition of PI3Kβ in the PI3K DM hearts but was not effective against PI3KαDN hearts (RPP: 74.2±4.5%, LVDP: 85.1±8.7% (n=7). Induction of downstream targets correlated with functional recovery, but PI3K DM had reduced Akt and GSK3β phosphorylation under aerobic conditions. Interestingly, PI3Kα DN hearts displayed increased glucose oxidation (PI3Kα DN: 10.2±1.1 vs wt: 6.9±1.1 nmol/g/min; p Conclusions: Protection from IR injury observed in PI3Kα DN hearts is dependent on alternate PI3K signaling, and suggests a redundancy between PI3Kβ and PI3Kγ isoforms. Increased glucose oxidation in the PI3KαDN hearts may also serve as a protective mechanism against IR injury, and decreased AMPK phosphorylation is indicative of decreased metabolic stress.
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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) | 0.000 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.016 | 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".