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Hoeksema, Marten A.; Gijbels, Marion J. J.; Bossche, Jan van den; Velden, Saskia van der; Sijm, Ayestha; Neele, Annette E.; Seijkens, Tom; Stöger, Lauran J.; Meiler, Svenja; Boshuizen, Marieke C. S.; Dallinga-Thie, Geesje M.; Levels, Johannes H. M.; Boon, Louis; Mullican, Shannon E.; Spann, Nathanael J.; Cleutjens, Jack P.; Glass, Chris K.; Lazar, Mitchell A.; Vries, Carlie J. M. de; Biessen, Erik A. L.; Daemen, Mat J. A. P.; Lutgens, Esther and Winther, Menno P. J. de (2014): Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions. In: Embo Molecular Medicine, Vol. 6, No. 9: pp. 1124-1132 [PDF, 1MB]

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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.

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