Open AccessTargeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions
Author(s) -
Hoeksema Marten A,
Gijbels Marion JJ,
Van den Bossche Jan,
Velden Saskia,
Sijm Ayestha,
Neele Annette E,
Seijkens Tom,
Stöger J Lauran,
Meiler Svenja,
Boshuizen Marieke CS,
DallingaThie Geesje M,
Levels Johannes HM,
Boon Louis,
Mullican Shan E,
Spann Nathanael J,
Cleutjens Jack P,
Glass Chris K,
Lazar Mitchell A,
Vries Carlie JM,
Biessen Erik AL,
Daemen Mat JAP,
Lutgens Esther,
Winther Menno PJ
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404170
Subject(s) - hdac3 , histone deacetylase , macrophage , cancer research , phenotype , inflammation , macrophage polarization , biology , downregulation and upregulation , immunology , hdac1 , immune system , microbiology and biotechnology , histone , genetics , gene , in vitro
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.