{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:04:02Z","timestamp":1791288242422,"version":"4.3.0"},"reference-count":67,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Italian Ministry of University and Research","doi-asserted-by":"publisher","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Italian Ministry of University and Research","doi-asserted-by":"publisher","award":["2017728JPK"],"award-info":[{"award-number":["2017728JPK"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009700","name":"Fondazione Gigi & Pupa Ferrari ONLUS","doi-asserted-by":"publisher","award":["FPF-14"],"award-info":[{"award-number":["FPF-14"]}],"id":[{"id":"10.13039\/501100009700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione IEO-MONZINO","id":[{"id":"https:\/\/ror.org\/006pq9r08","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013414","name":"R\u00e9gion Pays de la Loire","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013414","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nantes M\u00e9tropole"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>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\u2013glucose 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>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\u2019 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag199","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T13:51:25Z","timestamp":1788616285000},"source":"Crossref","is-referenced-by-count":0,"title":["Sirtuin 1 modulation unlocks the therapeutic potential of sodium\u2013glucose co-transporter 2 inhibitors in calcific aortic valve stenosis"],"prefix":"10.1093","author":[{"given":"Vincenza","family":"Valerio","sequence":"first","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Massaiu","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 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,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Chiesa","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika A","family":"Myasoedova","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rusconi","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bertolini","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS , Via privata Carlo Parea, 4, Milan 20138 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