Cytochrome P450‐Derived Epoxy Lipids of N‐3 PUFAs Protect the Heart From Ischemia‐Reperfusion Injury by Regulating Mitochondrial Sirtuin 3
Bibliographic record
Abstract
Objective Cytochrome P450 epoxygenases can metabolize dietary n‐3 polyunsaturated fatty acids (n‐3 PUFAs) to epoxy lipids, which have known cardioprotective effects; however, it remains unclear how this cardioprotection occurs. Our recent data demonstrate that cytochrome P450 epoxygenase‐derived metabolites of the n‐3 PUFA docosahexaenoic acid (DHA), 19,20‐epoxydocosapentaenoic acid (19,20‐EDP), exhibit protective effects toward cardiac mitochondria. Maintaining mitochondrial quality is essential to limit myocardial damage following ischemia‐reperfusion (IR) injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function and cardiac energy metabolism. We hypothesize that the cardioprotective mechanism(s) of 19,20‐EDP against IR injury involve(s) stimulating mitochondrial SIRT3. Methods Langendorff and isolated working heart perfusions were performed in male and female C57BL/6 mice to assess changes in cardiac function and energy metabolism in response to IR injury. Hearts were perfused with either vehicle, 19,20‐EDP (1 μM) and/or the SIRT3 inhibitor nicotinamide (30 μM) for a 20 min baseline perfusion, following which hearts were subjected to 30 min of global no flow ischemia and 40 min of reperfusion. Glucose and palmitate oxidation rates were measured to detect alterations in cardiac energy metabolism. Mitochondrial fractions were assessed for changes in SIRT3 activity and total lysine acetylation levels. Mitochondrial SIRT3 downstream targets were assessed in human ventricular tissues obtained from individuals with ischemic heart disease (IHD) included in the Human Explanted Heart Program and compared to non‐failing control hearts (NFC) collected from unused transplant donors through the Human Organ Procurement and Exchange Program at the University of Alberta. In addition, mitochondrial respiration was assessed in cardiac fibers isolated from the human tissues. Results Hearts perfused with 19,20‐EDP demonstrated improved post‐ischemic functional recovery, glucose oxidation and cardiac efficiency compared to control groups. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity and reduced global protein acetylation. We observed increased acetylation of the mitochondrial antioxidant superoxide dismutase 2 in tissues obtained from IHD human myocardium suggesting decreased antioxidant capacity. Treatment with 19,20‐EDP also markedly improved mitochondrial respiration in permeabilized human fibers obtained from IHD hearts. Importantly, the cardioprotective effects of 19,20‐EDP was abolished by the SIRT3 inhibitor nicotinamide. Conclusion We demonstrate that 19,20‐EDP‐mediated cardioprotective mechanisms against IR injury involve preservation of mitochondrial SIRT3 activity, which results in improved cardiac efficiency.
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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 | 0.001 |
| 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".