{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:33:54Z","timestamp":1787884434853,"version":"build-2784847793"},"reference-count":40,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T00:00:00Z","timestamp":1708560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974033"],"award-info":[{"award-number":["81974033"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmacology"],"published-print":{"date-parts":[[2024,4]]},"DOI":"10.1016\/j.ejphar.2024.176423","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T04:38:19Z","timestamp":1707885499000},"page":"176423","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":10,"special_numbering":"C","title":["SIRT6-mediated Runx2 downregulation inhibits osteogenic differentiation of human aortic valve interstitial cells in calcific aortic valve disease"],"prefix":"10.1016","volume":"968","author":[{"given":"Jiaqi","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunze","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Diao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buqing","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejphar.2024.176423_bib1","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1161\/CIRCULATIONAHA.117.027776","article-title":"A Rock and a hard Place: chiseling away at the multiple mechanisms of aortic stenosis","volume":"135","author":"Aikawa","year":"2017","journal-title":"Circulation"},{"key":"10.1016\/j.ejphar.2024.176423_bib2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.gde.2014.05.005","article-title":"Sirtuins, metabolism, and DNA repair","volume":"26","author":"Choi","year":"2014","journal-title":"Curr. Opin. Genet. Dev."},{"key":"10.1016\/j.ejphar.2024.176423_bib3","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1089\/ars.2017.7178","article-title":"SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection","volume":"28","author":"D'Onofrio","year":"2018","journal-title":"Antioxidants Redox Signal."},{"key":"10.1016\/j.ejphar.2024.176423_bib4","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1021\/bi802093g","article-title":"Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD","volume":"48","author":"Du","year":"2009","journal-title":"Biochemistry"},{"key":"10.1016\/j.ejphar.2024.176423_bib5","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0092-8674(00)80257-3","article-title":"Osf2\/Cbfa1: a transcriptional activator of osteoblast differentiation","volume":"89","author":"Ducy","year":"1997","journal-title":"Cell"},{"key":"10.1016\/j.ejphar.2024.176423_bib6","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nature08197","article-title":"Recent progress in the biology and physiology of sirtuins","volume":"460","author":"Finkel","year":"2009","journal-title":"Nature"},{"key":"10.1016\/j.ejphar.2024.176423_bib7","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1161\/CIRCRESAHA.120.318353","article-title":"SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis","volume":"128","author":"Grootaert","year":"2021","journal-title":"Circ. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib8","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1111\/febs.14055","article-title":"SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox-LDL condition","volume":"284","author":"He","year":"2017","journal-title":"FEBS J."},{"key":"10.1016\/j.ejphar.2024.176423_bib9","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1006\/scdb.2000.0188","article-title":"Role of Cbfa1 in osteoblast differentiation and function","volume":"11","author":"Karsenty","year":"2000","journal-title":"Semin. Cell Dev. Biol."},{"key":"10.1016\/j.ejphar.2024.176423_bib10","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1093\/eurheartj\/ehab757","article-title":"Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy","volume":"43","author":"Kraler","year":"2022","journal-title":"Eur. Heart J."},{"key":"10.1016\/j.ejphar.2024.176423_bib11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.tibs.2013.12.002","article-title":"Chromatin and beyond: the multitasking roles for SIRT6","volume":"39","author":"Kugel","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"10.1016\/j.ejphar.2024.176423_bib12","doi-asserted-by":"crossref","DOI":"10.1172\/JCI150051","article-title":"SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease","volume":"132","author":"Li","year":"2022","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.ejphar.2024.176423_bib13","article-title":"SIRT6 in senescence and aging-related cardiovascular diseases","volume":"9","author":"Li","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"10.1016\/j.ejphar.2024.176423_bib14","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1093\/eurheartj\/ehac037","article-title":"Endothelial cell-derived tetrahydrobiopterin prevents aortic valve calcification","volume":"43","author":"Liu","year":"2022","journal-title":"Eur. Heart J."},{"key":"10.1016\/j.ejphar.2024.176423_bib15","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.trsl.2016.02.005","article-title":"Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient mice","volume":"172","author":"Liu","year":"2016","journal-title":"Transl. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib16","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1172\/JCI82871","article-title":"Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity","volume":"125","author":"Masuda","year":"2015","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.ejphar.2024.176423_bib17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20070140","article-title":"Sirtuins in mammals: insights into their biological function","volume":"404","author":"Michan","year":"2007","journal-title":"Biochem. J."},{"key":"10.1016\/j.ejphar.2024.176423_bib18","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1091\/mbc.e05-01-0033","article-title":"Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins","volume":"16","author":"Michishita","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"10.1016\/j.ejphar.2024.176423_bib19","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1093\/cvr\/cvy111","article-title":"DNA methylation of a PLPP3 MIR transposon-based enhancer promotes an osteogenic programme in calcific aortic valve disease","volume":"114","author":"Mkannez","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1161\/CIRCRESAHA.115.306341","article-title":"Transcription factor Runx2 promotes aortic fibrosis and stiffness in type 2 diabetes mellitus","volume":"117","author":"Raaz","year":"2015","journal-title":"Circ. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib21","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1038\/s41598-018-22388-5","article-title":"Natural polyphenols as sirtuin 6 modulators","volume":"8","author":"Rahnasto-Rilla","year":"2018","journal-title":"Sci. Rep."},{"key":"10.1016\/j.ejphar.2024.176423_bib22","first-page":"1783","article-title":"Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group","volume":"124","author":"Rajamannan","year":"2011","journal-title":"Executive summary: Calcific aortic valve disease-2011 update. Circulation"},{"key":"10.1016\/j.ejphar.2024.176423_bib23","doi-asserted-by":"crossref","first-page":"A27","DOI":"10.1161\/atvb.34.suppl_1.27","article-title":"Role of sirtuin 6 in the initiation and progression of calcific aortic valve disease","volume":"34","author":"Roos","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"10.1016\/j.ejphar.2024.176423_bib24","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2020.105214","article-title":"Sirtuin 6: a potential therapeutic target for cardiovascular diseases","volume":"163","author":"Saiyang","year":"2021","journal-title":"Pharmacol. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib25","doi-asserted-by":"crossref","first-page":"15456","DOI":"10.1021\/bi011858j","article-title":"Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions","volume":"40","author":"Sauve","year":"2001","journal-title":"Biochemistry"},{"key":"10.1016\/j.ejphar.2024.176423_bib26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1161\/CIRCULATIONAHA.117.032291","article-title":"Spatiotemporal multi-omics mapping generates a molecular atlas of the aortic valve and reveals networks driving disease","volume":"138","author":"Schlotter","year":"2018","journal-title":"Circulation"},{"key":"10.1016\/j.ejphar.2024.176423_bib27","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cmet.2007.11.006","article-title":"Conserved metabolic regulatory functions of sirtuins","volume":"7","author":"Schwer","year":"2008","journal-title":"Cell Metabol."},{"key":"10.1016\/j.ejphar.2024.176423_bib28","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s13238-016-0257-6","article-title":"Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage","volume":"7","author":"Shao","year":"2016","journal-title":"Protein Cell"},{"key":"10.1016\/j.ejphar.2024.176423_bib29","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1161\/CIRCRESAHA.112.267237","article-title":"Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification","volume":"111","author":"Sun","year":"2012","journal-title":"Circ. Res."},{"key":"10.1016\/j.ejphar.2024.176423_bib30","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1038\/nm.2961","article-title":"The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun","volume":"18","author":"Sundaresan","year":"2012","journal-title":"Nat. Med."},{"key":"10.1016\/j.ejphar.2024.176423_bib31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.tibs.2010.07.009","article-title":"Chromatin regulation and genome maintenance by mammalian SIRT6","volume":"36","author":"Tennen","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"10.1016\/j.ejphar.2024.176423_bib32","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1002\/sctm.17-0137","article-title":"Osteogenic programming of human mesenchymal stem cells with highly efficient intracellular delivery of RUNX2","volume":"6","author":"Thiagarajan","year":"2017","journal-title":"Stem Cells Transl Med"},{"key":"10.1016\/j.ejphar.2024.176423_bib33","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1093\/eurheartj\/ehab316","article-title":"DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells","volume":"42","author":"Wang","year":"2021","journal-title":"Eur. Heart J."},{"key":"10.1016\/j.ejphar.2024.176423_bib34","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1093\/eurheartj\/ehv290","article-title":"Protective effects of sirtuins in cardiovascular diseases: from bench to bedside","volume":"36","author":"Winnik","year":"2015","journal-title":"Eur. Heart J."},{"key":"10.1016\/j.ejphar.2024.176423_bib35","doi-asserted-by":"crossref","DOI":"10.3390\/jcm11226733","article-title":"Global burden and improvement gap of non-rheumatic calcific aortic valve disease: 1990-2019 findings from global burden of disease study 2019","volume":"11","author":"Yang","year":"2022","journal-title":"J. Clin. Med."},{"key":"10.1016\/j.ejphar.2024.176423_bib36","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/j.jacc.2020.07.005","article-title":"Bicuspid aortic valve stenosis transcatheter aortic valve replacement registry, I","volume":"76","author":"Yoon","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"10.1016\/j.ejphar.2024.176423_bib37","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/anie.201610082","article-title":"Structural basis of sirtuin 6 activation by synthetic small molecules","volume":"56","author":"You","year":"2017","journal-title":"Angew Chem. Int. Ed. Engl."},{"key":"10.1016\/j.ejphar.2024.176423_bib38","doi-asserted-by":"crossref","first-page":"A366","DOI":"10.1161\/atvb.32.suppl_1.A366","article-title":"Sirtuin 6 reduces osteogenic signaling in aortic valve interstitial cells and vascular smooth muscle cells","volume":"32","author":"Zhang","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"10.1016\/j.ejphar.2024.176423_bib39","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s10517-018-3992-2","article-title":"Cellular mechanisms of aortic valve calcification","volume":"164","author":"Zhiduleva","year":"2018","journal-title":"Bull. Exp. Biol. Med."},{"key":"10.1016\/j.ejphar.2024.176423_bib40","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1038\/s41418-018-0240-2","article-title":"Long noncoding RNA lncAIS downregulation in mesenchymal stem cells is implicated in the pathogenesis of adolescent idiopathic scoliosis","volume":"26","author":"Zhuang","year":"2019","journal-title":"Cell Death Differ."}],"container-title":["European Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299924001110?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299924001110?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T23:31:01Z","timestamp":1757979061000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0014299924001110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":40,"alternative-id":["S0014299924001110"],"URL":"https:\/\/doi.org\/10.1016\/j.ejphar.2024.176423","relation":{},"ISSN":["0014-2999"],"issn-type":[{"value":"0014-2999","type":"print"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"SIRT6-mediated Runx2 downregulation inhibits osteogenic differentiation of human aortic valve interstitial cells in calcific aortic valve disease","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejphar.2024.176423","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"176423"}}