title: Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions.
abstract: Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. 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-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 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.
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Hoeksema
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Pathology, Maastricht University, Maastricht, The Netherlands Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Marion Jj
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Van den Bossche
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: van der Velden
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ayestha
authors.initials: A
authors.lastname: Sijm
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Neele
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Seijkens
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J Lauran
authors.initials: JL
authors.lastname: Stöger
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marieke Cs
authors.initials: MC
authors.lastname: Boshuizen
authors.affiliation: Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Johannes Hm
authors.initials: JH
authors.lastname: Levels
authors.affiliation: Bioceros BV, Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.affiliation: Department of Pathology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Cleutjens
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA.
authors.forename: Chris K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carlie Jm
authors.initials: CJ
authors.lastname: de Vries
authors.affiliation: Department of Pathology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Erik Al
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mat Jap
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands m.dewinther@amc.uva.nl.
authors.forename: Menno Pj
authors.initials: MP
authors.lastname: de Winther
mesh_terms: D000107:Acetylation; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D003094:Collagen; D006655:Histone Deacetylases; D053773:Transforming Growth Factor beta1; D000099186:Histone Deacetylase 3; C508961:Tgfb1 protein, mouse
keywords: atherosclerosis; epigenetics; fibrosis; lipids; macrophages