Abstract P034: Endothelin-1 Overexpression Exaggerates Diabetes-induced Endothelial Dysfunction by Altering Oxidative Stress Balance
Bibliographic record
Abstract
Objective: Increased endothelin (ET)-1 expression has been shown to cause endothelial dysfunction.Plasma ET-1 is increased in patients with diabetes.Since endothelial dysfunction often precedes vascular complications in diabetes, we sought to determine whether ET-1 contributes to diabetes-induced endothelial dysfunction. We hypothesized that overexpression of ET-1 in the endotheliumwill exaggerate diabetes-induced endothelial dysfunction. Method: Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6weekold male wild-type (WT) mice and in mice overexpressinghuman ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Blood glucose,plasma ET-1 levels, mesenteric artery (MA) reactivity, mitochondrial superoxide production in aorta and endothelial nitric oxide synthase (Nos3), superoxide dismutase 1 (Sod1) and 2 (Sod2) mRNA expression in MA were determined. Results: STZ-induced diabetes was confirmed by increased glycemia in WT(27.6±1.5 vs 10.7±1.1 μM, P<0.001)and eET-1 (23.2±1.0 vs 8.4±0.3 μM, P<0.001).Plasma ET-1 was increased in vehicle- (15.9±4.6 vs 0.6±0.04pg/mL, P<0.05) and STZ-treatedeET-1 (4.9±0.6 vs 0.8±0.1 pg/mL, P<0.05) compared to respective WT controls.Diabetes caused a reduction in vasodilatory responses to acetylcholine in WT (60.9±6.4% vs 83.9±3.4%,P<0.05), which was exaggerated in eET-1(48.6±5.1% vs 81.5±5.2% P<0.05). Mitochondrial superoxide production was increased by diabetes in WT (38.0±4.3 vs 21.6±2.3 RFU/μm2,P<0.05)and further augmented in eET-1 (49.8±1.7 RFU/μm2P<0.05).Nos3 expression was increased in vehicle-treatedeET-1 compared to WT(1.43±0.19 vs 1.00±0.10, P<0.05).Diabetes reduced Nos3 expression in eET-1 (0.75±0.08, P<0.05) but not in WT(1.08±0.09).Diabetes caused an increase in Sod1(1.52±0.17 vs 1.00±0.03, P<0.05) and Sod2 (1.32±0.17 vs 1.00±0.02, P<0.05) expression in WT (P<0.05) but not in eET-1. Conclusions: Increased levels of ET-1 exaggerate diabetes-induced endothelial dysfunction. This may be caused by a decrease in Nos3 expression, an increase in mitochondrial oxidative stress and a decrease in antioxidant capacity.
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".