Inhibition of Sirtuin‐1 Ameliorates Vascular Remodeling and Hypertension in SHR
Bibliographic record
Abstract
Sirtuin‐1 (SIRT1), class III histone deacetylase, has been shown to be overexpressed in hearts from spontaneously hypertensive rats (SHR). We recently showed that vascular smooth muscle cells (VSMC) from SHR exhibit enhanced expression of SIRT1 as compared to age‐matched Wister Kyoto (WKY) rats and contribute to the upregulation of Giα proteins implicated in the pathogenesis of hypertension. The present study was undertaken to investigate the role of upregulated SIRT1 expression in the pathogenesis of hypertension and associated vascular remodeling in SHR and to explore the underlying molecular mechanisms involved in this response. For this study, a selective inhibitor of SIRT1, EX‐527 (5mg/kg of body weight) was injected intraperitoneally into 8‐week‐old adult SHR and age‐matched WKY rats twice per week for 3 weeks. The blood pressure (BP) and heart rate was measured twice a week by the CODA™ non‐invasive tail cuff method. Treatment of SHR with Ex‐527 attenuated high BP by 50 mmHg and inhibited the augmented heart rate. The overexpression of Giα proteins in heart, VSMCs and aorta was also attenuated to the control levels by EX‐527. In addition, inhibition of SIRT1 also attenuated the enhanced levels of superoxide anion, NADPH oxidase activity, enhanced phosphorylation of c‐Src and ERK1/2/AKT in VSMCs isolated from EX‐527 treated SHR. Furthermore, the decreased expression of endothelial nitric oxide synthase (eNOS) in VSMCs and aorta from SHR was also restored to control levels by EX‐527. The hyperproliferation and hypertrophy exhibited by VSMC from SHR, the enhanced expression of cell cycle proteins cyclin D1 and cdk4 and Gqα /PLCβ1 proteins were also attenuated by EX‐527 treatment. These results suggest that the overexpression of SIRT1 contributes to the development of high BP and vascular remodeling in SHR and its inhibition improves hypertension and vascular remodeling. It may thus be suggested that inhibitors of SIRT1 may have the potential to be used as therapeutic agents in the treatment of cardiovascular complications associated with hypertension. Support or Funding Information Supported by grant from Canadian Institutes of Health Research (CIHR)
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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) | 0.001 | 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".