Abstract 429: PTP1B, a Link Between Endoplasmic Reticulum Stress and Endothelial Dysfunction
Bibliographic record
Abstract
Endothelial dysfunction is a common feature of diabetes and a major contributor to diabetic vascular complications. Despite aggressive diabetes management strategies, preventing diabetes-induced endothelial dysfunction remains a difficult challenge. Endothelium insulin resistance and endoplasmic reticulum (ER) stress have been reported to contribute to endothelial dysfunction. Protein tyrosine phosphatase 1B (PTP1B) is a phosphatase bound to the ER known to regulate insulin sensitivity and ER stress. We hypothesize that diabetes alters PTP1B regulation of endothelial cell function and that inhibiting PTP1B may allow a strategy to prevent diabetes-induced endothelial dysfunction. Using immuno-histochemistry we showed that PTP1B is expressed in the endothelial cells of human saphenous vein, and in human primary aortic endothelial cells. Western-blot and quantitative real-time PCR analysis revealed that diabetes increased PTP1B and ER stress markers expression (CHOP: 1.4±0.2, GRP78: 1.5±0.2, XBP1spliced: 2.1±0.3, XBP1: 1.4±0.2 fold changes), in human saphenous veins. Deletion of PTP1B in obese diabetic mice (db/db) significantly reduced the level of expression (mRNA) of ER stress markers in mouse aorta. Incubation of mouse aortic rings with tunicamycin (tunica) or thapsigargin (thapsi), two ER stress inducers, increased the level of expression of ER stress markers (mRNA) and significantly reduced endothelium-dependent relaxation. (Tunica: -17±5%, thapsi: -30±6%, vs. DMSO). NO synthase inhibition with LNAME completely abolished endothelium-dependent relaxation in vehicle and tunica-treated rings. Neither the reactive oxygen species (ROS) scavenger tempol, nor catalase restored endothelial function, in tunica-treated rings. This suggests that ER stress induces a reduction in NO bioavailability independent of ROS. Aortic rings from PTP1B KO mice were protected against ER stress-induced endothelial dysfunction and exhibited a modest increase in ER stress markers compared to control rings, in response to tunica. All together these data demonstrate that PTP1B deletion prevents ER stress-induced endothelial dysfunction and that targeting PTP1B might be a beneficial approach to restore diabetic endothelial dysfunction.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".