{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:01:10Z","timestamp":1792119670897,"version":"4.4.0"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Calcific aortic valve (AV) disease, characterized by AV sclerosis and calcification, is a major cause of death in the aging population; however, there are no effective medical therapies other than valve replacement. AV calcification preferentially occurs on the fibrosa side, exposed to disturbed flow (d-flow), whereas the ventricularis side exposed to predominantly stable flow remains protected by unclear mechanisms. Here, we tested the role of novel flow-sensitive UBE2C (ubiquitin E2 ligase C) and microRNA-483-3p (miR-483) in flow-dependent AV endothelial function and AV calcification.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>Human AV endothelial cells and fresh porcine AV leaflets were exposed to stable flow or d-flow. We found that UBE2C was upregulated by d-flow in human AV endothelial cells in the miR-483\u2013dependent manner. UBE2C mediated OS-induced endothelial inflammation and endothelial-mesenchymal transition by increasing the HIF-1\u03b1 (hypoxia-inducible factor-1\u03b1) level. UBE2C increased HIF-1\u03b1 by ubiquitinating and degrading its upstream regulator pVHL (von Hippel-Lindau protein). These in vitro findings were corroborated by immunostaining studies using diseased human AV leaflets. In addition, we found that reduction of miR-483 by d-flow led to increased UBE2C expression in human AV endothelial cells. The miR-483 mimic protected against endothelial inflammation and endothelial-mesenchymal transition in human AV endothelial cells and calcification of porcine AV leaflets by downregulating UBE2C. Moreover, treatment with the HIF-1\u03b1 inhibitor (PX478) significantly reduced porcine AV calcification in static and d-flow conditions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>These results suggest that miR-483 and UBE2C and pVHL are novel flow-sensitive anti- and pro-calcific AV disease molecules, respectively, that regulate the HIF-1\u03b1 pathway in AV. The miR-483 mimic and HIF-1\u03b1 pathway inhibitors may serve as potential therapeutics of calcific AV disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.118.312233","type":"journal-article","created":{"date-parts":[[2019,1,3]],"date-time":"2019-01-03T10:00:34Z","timestamp":1546509634000},"page":"467-481","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":77,"title":["Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1\u03b1 (Hypoxia-Inducible Factor-1\u03b1) Pathway in Endothelial Cells"],"prefix":"10.1161","volume":"39","author":[{"given":"Joan","family":"Fernandez Esmerats","sequence":"first","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Villa-Roel","sequence":"additional","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Gu","sequence":"additional","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Tausif","family":"Salim","sequence":"additional","affiliation":[{"name":"School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta (M.T.S., A.P.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ohh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Toronto, Ontario, Canada (M.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Robert","family":"Taylor","sequence":"additional","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"},{"name":"Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (W.R.T., H.J.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Nerem","sequence":"additional","affiliation":[{"name":"Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta (R.M.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit P.","family":"Yoganathan","sequence":"additional","affiliation":[{"name":"From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (J.F.E., N.V.-R., S.K., L.G., W.R.T., A.P.Y., H.J.)"},{"name":"School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta (M.T.S., A.P.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjoong","family":"Jo","sequence":"additional","affiliation":[{"name":"From the Wallace H. 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