Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions

EMBO Molecular Medicine

Marten A Hoeksema⁷  Marion JJ Gijbels⁷  Jan Van den Bossche⁷  Saskia van der Velden⁷  Ayestha Sijm⁷  Annette E Neele⁷  Tom Seijkens⁷  J Lauran Stöger⁷  Svenja Meiler⁷  Marieke CS Boshuizen⁷  Geesje M Dallinga-Thie³  Johannes HM Levels³  Louis Boon⁴  Shannon E Mullican⁵  Nathanael J Spann²  Jack P Cleutjens¹  Chris K Glass²  Mitchell A Lazar⁵  Carlie JM de Vries⁷  Erik AL Biessen¹  Mat JAP Daemen⁶  Esther Lutgens⁷ 

[1] Department of Pathology, Maastricht University, Maastricht, The Netherlands;Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA;Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Bioceros BV, Utrecht, The Netherlands;Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA;Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

关键词: atherosclerosis;    epigenetics;    fibrosis;    lipids;    macrophages;   

DOI  :  10.15252/emmm.201404170

来源: Wiley

【 摘 要 】

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.

Synopsis

Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.

• Myeloid Hdac3 deficiency promotes collagen deposition in atherosclerosis
• Macrophage Hdac3 deletion enhances TGF-β secretion thereby increasing collagen production by vascular smooth muscle cells and results in improved lipid handling by de-repression of PPARγ and LXR responses
• In humans, Hdac3 is upregulated in ruptured atherosclerotic lesions and is associated with inflammatory macrophages
• Fine-tuning of the macrophage phenotype by altering the epigenetic landscape can be applied to affect atherosclerotic disease outcome

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.