Abstract 58: Dicarbonyl Stress and Diabetic Heart Failure: The Role of Endothelial Cells
Bibliographic record
Abstract
Dicarbonyl stress (DS) caused by the accumulation of α-oxoaldehyde metabolites, like methylglyoxal (MG), leads to detrimental DNA and protein modifications. Under normal conditions, MG is detoxified by glyoxalase-1 (GLO1) and -2 enzymes, but this system fails in diabetes. While the role of DS in diabetic cardiomyopathy through changes in cardiomyocyte function has been well described, this study aimed to link DS with the development of endothelial dysfunction (ED) and early heart failure in diabetes. Transgenic mice that over-express GLO1 in endothelial cells (ECs) but not in cardiomyocytes, and their wild-type (WT) littermates were treated with STZ to induce hyperglycemia (WT-diabetic and GLO1-diabetic mice) or vehicle (non-diabetic controls). Hyperglycemia increased the circulating levels of ED markers in WT-diabetic (E-selectin 1.5-fold, ICAM 1.4-fold, and VCAM 1.1-fold), but not GLO1-diabetic mice. The number of vWF+ ECs in WT-diabetic hearts was reduced 2-fold compared to other groups, whereas GLO1 over-expression preserved capillary density. Cell death, determined by TUNEL staining, was greater in the hearts of WT-diabetic mice compared to all other groups. GLO1 over-expression resulted in reduced inflammation: TNF-α protein expression was increased in both diabetic groups (≥2-fold), but significantly less so in GLO1-diabetic mice (p=0.03). The preservation of ECs in GLO1-diabetic mice was associated with delayed signs of heart failure. At 4wk of hyperglycemia, WT-diabetic mice had reduced heart function compared to all other groups (p=0.04). At 8wk, cardiac function in GLO-diabetic mice was greater than in WT-diabetic mice, but both were reduced compared to non-diabetic controls (p=0.02; p=0.4). A possible mechanism for EC survival in GLO1 mice despite the presence of inflammation was examined in vitro using human aortic ECs. ECs exposed to high glucose or MG for 24h had increased apoptosis induced by TNF-α compared to cells treated only with TNF-α (by 2- and 3-fold, respectively), suggesting that reduced MG protects ECs from TNF-α mediated death. Taken together, these results suggest that DS in diabetes increases inflammation and ED, leading to the loss of ECs in the heart, which contributes to the development of heart failure.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".