PS 16-31 ENDOTHELIN-1 EXAGGERATES TYPE-1 DIABETES-ACCELERATED ATHEROSCLEROSIS THROUGH NADPH OXIDASES 1 AND 4
Bibliographic record
Abstract
Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe−/−) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Design and method: Six-week-old male Apoe−/− mice, eET-1/Apoe−/− and eET-1/Apoe−/− mice deficient in Nox1 (eET-1/Apoe−/−/Nox1y/−) or Nox4 (eET-1/Apoe−/−/Nox4−/−) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Results: Diabetic Apoe−/− mice presented an impaired maximal endothelium-dependent vasodilatory response to acetylcholine (21%), which was not observed in diabetic eET-1/Apoe−/−, eET-1/Apoe−/−/Nox1y/− or eET-1/Apoe−/−/Nox4−/− mice (99%). Endothelium-independent relaxation to the nitric oxide (NO) donor sodium nitroprusside was similar between groups. Blockade of NO synthase with L-NAME completely blunted endothelium-dependent relaxation to acetylcholine in diabetic eET-1/Apoe−/− mice, which was prevented by Nox1 but not by Nox4 knockout. ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe−/− mice, which was further exaggerated 1.2-fold by Nox4 but not Nox1 knockout. ET-1 overexpression exaggerated > 2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe−/− mice, which was reduced ∼40% by Nox1 and Nox4 knockout. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.
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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) | 0.000 | 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) | 0.003 | 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".