Effects of inhibition of myocardial extracellular-responsive kinase and P38 mitogen-activated protein kinase on mechanical function of rat hearts after prolonged hypothermic ischemia
Bibliographic record
Abstract
BACKGROUND: Mitogen-activated protein kinases (MAPKs), including extracellular-responsive kinase (ERK) and p38 MAPK, are activated by stresses associated with hypothermia-rewarming and ischemia-reperfusion. Their activation in heart is associated with beneficial (preconditioning) and adverse effects (apoptosis and impaired contractility). This study determined whether ERK and p38 MAPK activities are altered by hypothermic ischemia and normothermic reperfusion and the consequences of their inhibition on recovery of myocardial function. METHODS: Left ventricular work (L x min(-1) x mm Hg) was assessed during normothermic perfusion (30 min) of isolated rat hearts that were either freshly excised or previously subjected to hypothermic storage (8 hr, 3 degrees C) and rewarming (10 min, 37 degrees C) before normothermic reperfusion (30 min). Phospho-specific immunoblot analysis of p38 MAPK was performed in hearts and various cultured cells. RESULTS: Compared with fresh hearts, hearts subjected to hypothermia and rewarming demonstrated impaired left ventricular work (1.96+/-0.53, n=12 vs. 8.37+/-0.46, n=4, <0.05) during reperfusion. The ERK inhibitor, PD98059 (20 microM), present during storage and rewarming, caused modest improvement (3.66+/-0.75, n=9, <0.05). The p38 MAPK inhibitor, SB202190 (10 microM), when present during reperfusion, improved recovery (to 6.12+/-0.75, n=6, <0.05); it was ineffective if present only during rewarming (1.52+/-0.88, n=4). In rat2 fibroblasts, hypothermia and rewarming activated p38 MAPK and its downstream kinase MAPK-activated protein kinase 2, but not c-Jun N-terminal kinase/stress-activated protein kinase. CONCLUSIONS: Myocardial p38 MAPK and MAPK-activated protein kinase 2 are stimulated by hypothermia, ischemia, and rewarming and are detrimental to recovery of mechanical function of hearts subjected to prolonged hypothermic storage. Inhibition of p38 MAPK may be useful in protocols to improve the recovery of mechanical function of cold-stored hearts.
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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 | 0.000 | 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 | 0.000 |
| 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".