The Obesity-Related Peptide Leptin Sensitizes Cardiac Mitochondria to Calcium-Induced Permeability Transition Pore Opening and Apoptosis
Bibliographic record
Abstract
The obesity-related 16 kDa peptide leptin is synthesized primarily in white adipocytes although its production has been reported in other tissues including the heart. There is emerging evidence that leptin may contribute to cardiac pathology especially that related to myocardial remodelling and heart failure. In view of the importance of mitochondria to these processes, the goal of the present study is to determine the effect of leptin on mitochondria permeability transition pore opening and the potential consequence in terms of development of apoptosis. Experiments were performed using neonatal rat ventricular myocytes exposed to 3.1 nM (50 ng/ml) leptin for 24 hours. Mitochondrial transition pore opening was analyzed as the capacity of mitochondria to retain the dye calcein-AM in presence of 200 µM CaCl2. Leptin significantly increased pore opening although the effect was markedly more pronounced in digitonin-permeabilized myocytes in the presence of calcium with both effects prevented by the transition pore inhibitor sanglifehrin A. These effects were associated with increased apoptosis as evidenced by increased TUNEL staining and caspase 3 activity, both of which were prevented by the transition pore inhibitor sanglifehrin A. Leptin enhanced Stat3 activation whereas a Stat 3 inhibitor peptide prevented leptin-induced mitochondrial transition pore opening as well as the hypertrophic and pro-apoptotic effects of the peptide. Inhibition of the RhoA/ROCK pathway prevented the hypertrophic response to leptin but had no effect on increased pore opening following leptin administration. We conclude that leptin can enhance calcium-mediated, Stat3-dependent pro-apoptotic effects as a result of increased mitochondrial transition pore opening and independently of its hypertrophic actions. Leptin may therefore contribute to mitochondrial dysfunction and the development of apoptosis in the diseased myocardium particularly under conditions of excessive intracellular calcium accumulation.
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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) | 0.000 | 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 | 0.001 |
| 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".