Abstract 367: A Nox4 Inhibitor, GKT 137831, Decreases Aldosterone Synthesis, Adiposity and Vascular Contractility in a Murine Model of Diabetes.
Bibliographic record
Abstract
Nox4 is expressed in many cell types including vascular cells and adipocytes. Expression of Nox4 is increased in cardiovascular diseases, such as hypertension and diabetes. Despite the advancement in the understanding of Nox4 biochemistry and its mechanisms of regulation, the pathophysiological role of Nox4 remains elusive and controversial. We recently demonstrated that adipocytes produce aldosterone, an effect that was exacerbated in diabetes and contributed to vascular dysfunction. Here we postulated that Nox4 plays a role on adipocyte-derived aldosterone production, leading to vascular dysfunction, during diabetes. Studies were performed in db/m (control) and db/db mice (a murine model of diabetes). Control and db/db mice were divided into 3 groups: Group 1, no treatment, Group 2, treatment with 20 mg (low dose) and Group 3, 60 mg (high dose) of GKT137831 (GKT) (Nox4 inhibitor) for 16 weeks. Blood pressure was measured by tail-cuff. Aldosterone (aldo) levels were measured in plasma and cell culture media from mature adipocytes extracted from all groups. Mesenteric arteries were obtained from all groups to study vascular responses to acetylcholine, a nitric oxide donor (DEA-NO) and norepinephrine (NE) by myography. Body weight was increased in db/db (61.8g ± 0.95) versus control (33.5g ± 0.72) mice, p<0.05. GKT treatment did not alter body weight in db/m or db/db mice. Blood pressure levels were similar in all groups. Epididymal adiposity was increased in db/db mice (0.098g ± 0.16 vs. 0.067g ± 0.15, p<0.05). Aldo levels were increased in plasma (pg/mL: 518 ± 67 vs. 272 ± 30, p<0.05) and media from mature adipocytes (pg/mL/μg RNA: 1964 ± 213 vs. 388 ± 55, p<0.001). GKT treatment (high dose) decreased adiposity (0.07g ± 0.05) and aldo levels in plasma (390 ± 41 pg/mL) and media from mature adipocytes (577 ± 91 pg/mL), p<0.01. Endothelial dysfunction observed in db/db mice was not affected by GKT treatment. However, GKT treatment induced a decrease on NE-induced contraction in mesenteric arteries from db/db mice (pD2 values: db/db vs. db/db high dose, 6.4±0.1 vs. 5.6 ± 0.1, p<0.001). Our findings suggest a role for Nox4 in adipocyte-derived aldo production and vascular reactivity in db/d mice. Such Nox4-related processes may be important in obesity-diabetes.
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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) | 0.004 | 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".