Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis
Abstract
Aims 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 aortic valve fibro-calcification processes. Methods and results RNA-seq data of human aortic valve specimens were collected from the ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VICs) were generated by clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9). Real-time PCR, immunofluorescence, and calcification assays were used to characterize 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 sulfonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. The cumulative incidence of hospitalization for non-rheumatic aortic valve disease was estimated accounting for death as a competing event, and Fine and Gray models were used to estimate subdistribution hazard ratios. RNA-seq showed that SIRT1 could be an upstream regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular matrix remodelling, 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 the impact of SGLT2i on calcification, we showed that VICs cultured in endothelial medium treated with SGLT2i exhibited reduced calcification, which was associated with increased endothelial nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that the SGLT2i-treated group had a lower incidence of hospitalized patients for non-rheumatic aortic valve disease compared to the SU-treated group. Conclusion Our data identify SIRT1 as an upstream regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow aortic valve degeneration through SIRT1 modulation. These findings support SGLT2i as a potential therapeutic strategy for AS prevention and care.
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BibTeX
@article{valerio2026sirtuin,
title = {{Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis}},
author = {Vincenza Valerio and Ilaria Massaiu and Matteo Franchi and Antoine Rimbert and Zoé Begué-Racapé and Mattia Chiesa and Veronika Myasoedova and Valentina Rusconi and Francesca Bertolini and Donato de Giorgi and Alice Bonomi and Sergio Pirola and Marco Zanobini and Paola Di Pietro and Albino Carrizzo and Michele Ciccarelli and Romain Capoulade and Stefano Genovese and Paolo Poggio},
journal = {Cardiovascular Research},
year = {2026},
month = sep,
doi = {10.1093/cvr/cvag199},
url = {https://hal.science/hal-05763879v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis
AU - Vincenza Valerio
AU - Ilaria Massaiu
AU - Matteo Franchi
AU - Antoine Rimbert
AU - Zoé Begué-Racapé
AU - Mattia Chiesa
AU - Veronika Myasoedova
AU - Valentina Rusconi
AU - Francesca Bertolini
AU - Donato de Giorgi
AU - Alice Bonomi
AU - Sergio Pirola
AU - Marco Zanobini
AU - Paola Di Pietro
AU - Albino Carrizzo
AU - Michele Ciccarelli
AU - Romain Capoulade
AU - Stefano Genovese
AU - Paolo Poggio
PY - 2026
DA - 2026/09/08
JO - Cardiovascular Research
DO - 10.1093/cvr/cvag199
UR - https://hal.science/hal-05763879v1
AB - Aims 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 aortic valve fibro-calcification processes. Methods and results RNA-seq data of human aortic valve specimens were collected from the ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VICs) were generated by clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9). Real-time PCR, immunofluorescence, and calcification assays were used to characterize 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 sulfonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. The cumulative incidence of hospitalization for non-rheumatic aortic valve disease was estimated accounting for death as a competing event, and Fine and Gray models were used to estimate subdistribution hazard ratios. RNA-seq showed that SIRT1 could be an upstream regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular matrix remodelling, 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 the impact of SGLT2i on calcification, we showed that VICs cultured in endothelial medium treated with SGLT2i exhibited reduced calcification, which was associated with increased endothelial nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that the SGLT2i-treated group had a lower incidence of hospitalized patients for non-rheumatic aortic valve disease compared to the SU-treated group. Conclusion Our data identify SIRT1 as an upstream regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow aortic valve degeneration through SIRT1 modulation. These findings support SGLT2i as a potential therapeutic strategy for AS prevention and care.
SN - 0008-6363
ER -