Sirtuin1 inhibitor attenuates hypertension in spontaneously hypertensive rats: role of Giα proteins and nitroxidative stress
Bibliographic record
Abstract
BACKGROUND: We recently showed that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) exhibit overexpression of Sirtuin1 (Sirt1) that contributes to the enhanced expression of Giα proteins implicated in the development of hypertension in SHR. METHOD: The present study investigated if the inhibition of Sirt1 could also ameliorate hypertension in SHR and explore the underlying molecular mechanisms. For this study, a selective inhibitor of Sirt1, EX-527 (5 mg/kg of body weight), was injected intraperitoneally into 8-week-old SHR and age-matched Wistar Kyoto (WKY) rats twice per week for 3 weeks. The blood pressure (BP) and heart rate was measured twice a week by the CODA noninvasive tail cuff method. RESULTS: The high BP and augmented heart rate in SHR was significantly attenuated by EX-527 treatment, which was associated with the suppression of the overexpression of Sirt1 and Giα proteins in heart, VSMC and aorta. In addition, the enhanced levels of superoxide anion, NADPH oxidase activity, overexpression of NADPH oxidase subunits and FOXO1 were attenuated and the decreased levels of endothelial nitric oxide synthase (eNOS), nitric oxide and increased levels of peroxynitrite (ONOO-) and tyrosine nitration in VSMC from SHR were restored to control levels by EX-527 treatment. Furthermore, knockdown of FOXO1 by siRNA also attenuated the overexpression of Giα-2 and NADPH oxidase subunit proteins and restored the decreased expression of eNOS in VSMC from SHR. CONCLUSION: These results suggest that the inhibition of overexpressed Sirt1 and its target FOXO1 through decreasing the enhanced levels of Giα proteins and nitro-oxidative stress attenuates the high BP in SHR.
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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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".