{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:03:28Z","timestamp":1790705008327,"version":"4.1.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Transdifferentiation of adventitial fibroblasts (AFs) into myofibroblasts plays a critical role during the vascular remodeling that occurs during atherosclerosis, restenosis, and aortic aneurysm. The ubiquitination\/deubiquitination regulatory system is essential for the quality control of proteins. The involvement of ubiquitination\/deubiquitination during AF transdifferentiation remains largely unknown. In this study, we determined the role of cylindromatosis (CYLD), a deubiquitinase, in the process of AF differentiation and activation in vitro and in vivo.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              Transforming growth factor-\u03b21 and homocysteine, 2 known inducers of AF transdifferentiation, greatly upregulated CYLD expression in a time- and dose-dependent manner. The silencing of CYLD significantly inhibited AF transdifferentiation and activation as evidenced by the expression of contractile proteins, the production of the proinflammatory cytokines MCP-1 (monocyte chemotactic protein 1) and IL-6 (interleukin-6), the deposition of extracellular matrix, and cell migration. We further asked whether CYLD mediates AF activation via the regulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) as it is an essential factor during AF transdifferentiation. Indeed, the silencing of CYLD repressed transforming growth factor-\u03b21\u2013induced and homocysteine-induced Nox4 upregulation and reactive oxygen species production, whereas Nox4 overexpression greatly rescued the inhibitory effect on AF activation by CYLD silencing. Most interestingly, transforming growth factor-\u03b21 and homocysteine repressed Nox4 ubiquitination and prolonged the half-life of Nox4. Moreover, Nox4 was deubiquitinated via a direct interaction with the ubiquitin-specific protease domain of CYLD. In accordance, hyperhomocysteinemia significantly increased adventitial CYLD and Nox4 expression, promoted AF transdifferentiation, and aggravated CaPO\n              <jats:sub>4<\/jats:sub>\n              -induced abdominal aortic aneurysm in mice. These effects were abolished in CYLD\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>CYLD contributes to the transdifferentiation of AFs via deubiquitinating Nox4 and may play a role in vascular remodeling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.117.309859","type":"journal-article","created":{"date-parts":[[2017,7,28]],"date-time":"2017-07-28T01:00:56Z","timestamp":1501203656000},"page":"1698-1709","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":69,"title":["CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Contributing to Adventitial Remodeling"],"prefix":"10.1161","volume":"37","author":[{"given":"Bing","family":"Yu","sequence":"first","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Fu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingbao","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. 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China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (B.Y., Z.L., Y.F., Y.W., L.Z., Z.C., F.Y., X.W., W.K.); and State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, P. R. 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