Abstract 3552: Pharmacological Inhibition or Genetic Disruption of Protein Tyrosine Phosphatase 1B Attenuates both Myocardial and Endothelial Dysfunction in Mice with Heart Failure
Bibliographic record
Abstract
We have shown previously that acute, in vitro inhibition of protein tyrosine phosphatase 1B (PTP1B) improved endothelial function of peripheral resistance arteries in mice with chronic heart failure (CHF), as demonstrated by the restored flow-mediated, NO-dependent vasodila-tation (FMD). This is most likely due to increased tyrosine phosphorylation pathways involved in shear stress-induced activation of eNOS. The present study evaluates the impact of chronic pharmacological inhibition or genetic disruption of PTP1B, on cardiac and endothelial dysfunction in CHF mice. CHF was induced by coronary ligation, either in C57BL/6 mice, or in wild type (WT) or PTP1B-deficient (PTP1B−/−) BALB/c mice. CHF mice (either C57BL/6 or BALB/c WT) were untreated or treated with the PTP1B inhibitor AS279 (60 mg/kg/day) for 2 months. Mice were then anesthetized with isoflurane for echocardiographic evaluation of left ventricular (LV) function and remodeling. After euthanasia, small mesenteric artery segments were isolated and mounted in an arteriograph for the evaluation of FMD. Echocardiographic results are shown in the Table . In parallel, in vitro vascular studies showed that chronic AS279 restored FMD both in C57BL/6 (max FMD: control: 17±2, n=9; CHF untreated: -1±1, n=9; CHF + AS279: 14±2%, n=19; p<0.01 vs. CHF untreated) and BALB/c CHF mice (Control: 29±4, n=16; CHF untreated: 7±1, n=5; CHF + AS279: 24±6%, n=7; p<0.01 vs. CHF untreated). Compared to CHF WT, FMD was also increased in PTP1B−/− CHF mice (WT: 7±1, n=5, PTP1B−/−: 16±6%, n=6, p<0.05). Additionally, in vitro downregulation of PTP1B (by a 3 day incubation with shRNA) also increased FMD in arteries isolated from CHF mice (max FMD: untreated: 6±2; scrambled shRNA: 7±2; shRNA PTP1B: 27±2%, p<0.01). Thus, chronic pharmacological inhibition or genetic disruption of PTP1B both restores endothelial function and improves cardiac dysfunction and remodeling, suggesting that this enzyme may be a new target for the treatment of CHF. Echocardiographic results in mice with 2 months CHF
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".