Pharmacologic Inhibition or Genetic Deletion of Soluble Epoxide Hydrolase Improves Survival Following Myocardial Infarction in Aged Mice
Bibliographic record
Abstract
Objective Myocardial infarction (MI) accounts for a significant proportion of death and disability in aged individuals. CYP450 metabolism of n−6 PUFA arachidonic acid results in formation of numerous metabolites, called eicosanoids, that exhibit a wide range of cellular effects. Previous studies demonstrate eicosanoids can induce alterations to the mitochondria resulting in preserved cardiac function following ischemic injury. These metabolites are further metabolised by the enzyme soluble epoxide hydrolase (sEH) reducing their endogenous activity. This study investigated post‐ischemic cardiac function in aged mice with either genetic deletion or pharmacologic inhibition of sEH. Furthermore, a primary component of this study was to elucidate potential sex differences between male and female mice undergoing the experimental protocol. Methods Male and female WT and sEH null mice averaging 15 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD). On the day of surgery, WT mice were given either vehicle (0.1% DMSO) or sEH inhibitor t AUCB (10 mg/ml dissolved in 0.1% DMSO) in drinking water for 28 days ad libitum . Cardiac function was assessed at baseline, 7 days and 28 days post‐MI by echocardiography and electrocardiogram. Protein expression was determined using immunoblotting techniques while mitochondrial enzymatic activities were assessed by spectrophotometry. Mitochondrial respiration in cardiac fibres was measured using a Clark‐type electrode. A full metabolite profile was determined in control and 28‐day post‐MI hearts by LCMS/MS. Results Pharmacological inhibition or genetic deletion of sEH was associated with fundamental changes in the n−3 and n−6 PUFA metabolite profile in cardiac tissue, correlating with better diastolic function, preserved mitochondrial respiration and overall improved survival at 28‐days post‐MI. Conclusions These data suggest that pharmacologic inhibition or genetic deletion of sEH elicits fundamental changes in the aged myocardium following long‐term ischemic injury. Support or Funding Information This research is supported by grants from the Canadian Heart and Stroke Foundation and Canadian Institute of Health Research. LJ is supported by a graduate studentship from Alberta Innovates‐Health Solutions. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.001 | 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 | 0.001 |
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".