Imbalanced synthesis of cyclooxygenase‐derived thromboxane A<sub>2</sub> and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: Thoracic aortic dissection is a life-threatening complication of Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1. We have demonstrated that nitric oxide-mediated endothelial-dependent relaxation is impaired in the thoracic aorta in Marfan syndrome. In the present study, we determined whether the cyclooxygenase (COX)-pathway is involved in the compromised aortic vasomotor function. EXPERIMENTAL APPROACH: Thoracic aortae from mice at 3, 6 and 9 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), 'Marfan', n=35), were compared with those from age-matched controls (n=35). KEY RESULTS: Isometric force measurement revealed that preincubation with indomethacin, a non-specific COX inhibitor, but not valeryl salicylate, a specific COX-1 inhibitor, improved the phenylephrine-induced contractions (at 6 months, EC(50) and E(max) were increased 4.5-fold and by 45%, respectively) in Marfan aortae. Sensitivity to acetylcholine-induced relaxation was improved 10-fold. Blockade of the thromboxane-endoperoxide receptor by SQ-29548 did not affect phenylephrine-mediated contractions in Marfan aortae, although they did respond to the thromboxane analogue, U46619. From 6 months on, phenylephrine-induced secretion of prostacyclin and thromboxane A(2) in Marfan aortae was 200% and 40%, respectively, of those in controls. Reduced COX-1 expression was detected in Marfan aortae at 3 and 9 months, whilst COX-2 expression was increased from 3 months on. CONCLUSIONS AND IMPLICATIONS: The compromised vasomotor function in Marfan thoracic aortae is associated with an imbalanced synthesis of thromboxane A(2) and prostacyclin resulting from the differential protein expression of COX-1 and COX-2.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".