{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:27:35Z","timestamp":1790515655243,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Aortic valve disease, including calcification, affects &gt;2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of\n              <jats:italic>Tgf\u03b21<\/jats:italic>\n              in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.115.306091","type":"journal-article","created":{"date-parts":[[2015,12,4]],"date-time":"2015-12-04T03:09:29Z","timestamp":1449198569000},"page":"328-338","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["Valve Endothelial Cell\u2013Derived Tgf\u03b21 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification"],"prefix":"10.1161","volume":"36","author":[{"given":"Danielle J.","family":"Huk","sequence":"first","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair F.","family":"Austin","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tori E.","family":"Horne","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Hinton","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Ray","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald D.","family":"Heistad","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. Miller School of Medicine, Miami, FL (D.J.H.); Center for Cardiovascular Research and The Heart Center at Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (D.J.H., B.F.A., T.E.H., J.L.); Division of Cardiology, The Heart Institute, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH (R.B.H.); Battelle Center for Mathematical Medicine, Nationwide Children\u2019s Hospital Research Institute, Columbus, OH (W.C..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Lincoln","sequence":"additional","affiliation":[{"name":"From the Molecular and Cellular Pharmacology Graduate Program, Leonard M. 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