NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition
Bibliographic record
Abstract
AIMS: The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na(+)-H(+) exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 microM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[(3)H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. CONCLUSION: The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.
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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) | 0.002 | 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 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".