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EMBO Mol Med. 2014 Sep;6(9):1124-32. doi: 10.15252/emmm.201404170.

Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions.

Author information

1
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2
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.
3
Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
4
Bioceros BV, Utrecht, The Netherlands.
5
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
6
Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA.
7
Department of Pathology, Maastricht University, Maastricht, The Netherlands.
8
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
9
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.
10
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands m.dewinther@amc.uva.nl.

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.

KEYWORDS:

atherosclerosis; epigenetics; fibrosis; lipids; macrophages

PMID:
25007801
PMCID:
PMC4197860
DOI:
10.15252/emmm.201404170
[Indexed for MEDLINE]
Free PMC Article

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