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Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti\u2010inflammatory wound healing characteristics and showed improved lipid handling. The pro\u2010fibrotic phenotype was directly linked to epigenetic regulation of the\n                    <jats:italic>Tgfb1<\/jats:italic>\n                    locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans,\n                    <jats:italic>HDAC3<\/jats:italic>\n                    was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and\n                    <jats:italic>HDAC3<\/jats:italic>\n                    expression inversely correlated with pro\u2010fibrotic\n                    <jats:italic>TGFB1<\/jats:italic>\n                    expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404170","type":"journal-article","created":{"date-parts":[[2014,7,10]],"date-time":"2014-07-10T00:48:23Z","timestamp":1404953303000},"page":"1124-1132","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":166,"title":["Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions"],"prefix":"10.1038","volume":"6","author":[{"given":"Marten A","family":"Hoeksema","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion JJ","family":"Gijbels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Van den Bossche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"van der Velden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayestha","family":"Sijm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette E","family":"Neele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Seijkens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Lauran","family":"St\u00f6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Meiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke CS","family":"Boshuizen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geesje M","family":"Dallinga\u2010Thie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes HM","family":"Levels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon E","family":"Mullican","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathanael J","family":"Spann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack P","family":"Cleutjens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris K","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell A","family":"Lazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlie JM","family":"de Vries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik AL","family":"Biessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat JAP","family":"Daemen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Lutgens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno PJ","family":"de Winther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,7,9]]},"reference":[{"key":"BFEMMM201404170_CR1","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nrd3674","volume":"11","author":"CH Arrowsmith","year":"2012","unstructured":"Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. 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