Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis

Clicks: 18
ID: 327853
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Steady

Ranked #86 of 164 articles by views in cardiovascular research

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 164 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract Background Calcific aortic valve stenosis (AS) affects 3% of older adults and lacks medical treatment. The deacetylase Sirtuin 1 (SIRT1) could be involved in many pathways linked to AS progression. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucose-lowering agents, have been shown to reduce cardiovascular events (likely via SIRT1), but their possible benefits in AS are unknown. Our study aims to uncover the role of SIRT1 in AS progression and assess the benefit of SGLT2i to slow down the aortic valve fibro-calcification processes. Methods RNA-seq data of human aortic valve specimens were collected from ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VIC) were generated by CRISPR/Cas9. Real-time PCR, immunofluorescence, and calcification assays were used to characterized mutant VICs. Conditioned medium experiments were implemented to evaluate SGLT2i effect on cellular cross-talk and calcification. Diabetic patients’ data from the Lombardy regional healthcare database, treated with sulphonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. Cumulative incidence of hospitalization for non-rheumatic aortic valve disease was assessed by Kaplan-Meier and multivariable Cox proportional hazards models were used to estimate hazard ratios. Results RNA-seq showed that SIRT1 could be a master regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular-matrix remodeling and calcification by modulating key transcription factors. Moreover, calcification assays further support this role, revealing an increased calcification in SIRT1 KD VICs and a concomitant decrease in VIC SIRT1 Over when compared to wild type. Then, exploring SGLT2i impact on calcification, we showed that VICs cultured in SGLT2i-treated-endothelial medium exhibited reduced calcification associated with endothelial-increased nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that SGLT2i-treated group had a lower incidence of hospitalized patients for non-rheumatic aortic valve disease compared to SU-treated group. Conclusions Our data identify SIRT1 as a key regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow the aortic valve degeneration through SIRT1 modulation. These findings highlight SGLT2i as a promising therapeutic option for AS prevention and care. Clinical Perspectives What is new? Sirtuin 1 (SIRT1) downregulation is linked to the progression of aortic stenosis (AS) pathological processes and plays a crucial role in mitigating oxidative stress, fibrosis, and calcification. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) treatment of valve endothelial cells results in the secretion of protective factors that reduce valve interstitial cell calcification, highlighting the valuable role of endothelial health in preventing valve degeneration. Real-world data indicate that the use of SGLT2i is associated with a lower incidence of hospitalization rate for aortic valve disease as compared to sulfonylureas, suggesting a protective effect against AS in diabetic patients. What are the clinical implications? This study highlights the potential of restoring SIRT1 activity as a therapeutic strategy to mitigate pro-calcific and pro-fibrotic processes in AS. SGLT2i may offer a breakthrough therapeutic option for AS, a condition currently lacking effective pharmacological treatments, providing new hope for slowing disease progression and improving clinical outcomes.
Reference Key
openalex_W4408230698 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Vincenza Valerio, Ilaria Massaiu, Matteo Franchi, Antoine Rimbert, Zoé Begué-Racapé, Mattia Chiesa, Veronika A. Myasoedova, Valentina Rusconi, Francesca Bertolini, Donato De Giorgi, Alice Bonomi, Sergio Pirola, Marco Zanobini, Paola Di Pietro, Albino Carrizzo, Michele Ciccarelli, Romain Capoulade, Stefano Genovese, Paolo Poggio
Are you one of these authors? Claim your profile
Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag199
URL
https://doi.org/10.1093/cvr/cvag199
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.