20‐HETE Antagonism Reduces Left Ventricular Remodeling Post‐Myocardial Infarction
Bibliographic record
Abstract
20‐Hydroxyeicosatetraenoic acid (20‐HETE) is a cytochrome p450‐derived eicosanoid that stimulates endothelial dysfunction and inflammation via binding to its receptor, GPR75 (GPCR‐Gα q/11 ). Increased 20‐HETE in animals and humans is associated with hypertension, stroke, myocardial infarction (MI), metabolic syndrome (MetS), and increased reactive oxygen species (ROS). However, investigated effectiveness of 20‐HETE antagonists on ROS generation and MI size has been limited by short‐term follow up and administration of inhibitors prior to onset of MI only in healthy animals. Here, we evaluated the effect of a 20‐HETE antagonist, 20‐SOLA, administered at onset of reperfusion on post MI remodeling 48 hours and 8 weeks after reperfusion in normal (SD) and MetS (JCR:LA‐cp) rats. 20‐HETE was elevated in response to ischemia and more so during reperfusion; this elevation was greater in MetS (ischemia: 2‐fold SD and JCR; reperfusion: 3‐fold SD, 4‐fold JCR). MI size was markedly greater in JCR vs. SD rate (50% vs. 25% of LV). Treatment with 20‐SOLA significantly decreased MI size in both SD (~50%) and JCR (~65%) rats. Equivalent results were obtained in animals treated with GPR75‐shRNA‐Lnv at onset of reperfusions. 20‐SOLA improved coronary blood flow (1.00 ± 0.01 to 1.84 ± 0.03 mg/ml/g in SD to 0.99 ± 0.03 to 1.75±0.01 mg/ml/g in JCR). Mechanistically, smaller MI size in 20‐SOLA‐treated animals correlated with decreased ROS production in JCR rats (90%). Furthermore, survival and left ventricular (LV) function were preserved 8 weeks post MI in 20‐SOLA‐treated animals (ejection fraction (EF) = 80.5% (SD, 100% survival) and 82.5% (JCR, 100% survival)). This correlated with decreased ROS, preserved myocyte morphology, and preserved intact collagen. Differential activation of MMPs in SD vs. JCR rats vs. 20‐SOLA‐treated animals underlie the observed morphological, structural and functional changes. ROS production was decreased in JCR rats treated with a NOX inhibitor (~60%); NOX inhibition also markedly reduced MI size at 48h (60%) and preserved LV function at 8 weeks (EF = 74%, 85% survival) vs. non‐treated rats demonstrating an important role for NOX‐derived ROS in determining MI size and long‐term post‐MI remodeling. In the aggregate, these results indicated that targeting 20‐HETE actions may be an important consideration in prevention of detrimental LV remodeling and mortality post MI. Funding: HL093052. Support or Funding Information Funding: HL093052 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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".