Inhibiting epigenetic enzymes to improve atherogenic macrophage functions

• Published in: Biochemical and biophysical research communications Vol. 455; no. 3-4; pp. 396 - 402
• Main Authors: Van den Bossche, Jan, Neele, Annette E., Hoeksema, Marten A., de Heij, Femke, Boshuizen, Marieke C.S., van der Velden, Saskia, de Boer, Vincent C., Reedquist, Kris A., de Winther, Menno P.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2014
• Subjects: Acetylation; Animals; Apoptosis; Atherosclerosis; Atherosclerosis - metabolism; Cell Line; Chromatin - metabolism; Chromatin modifying enzymes (CME); Epigenesis, Genetic; Epigenetics; Femur - metabolism; Foam Cells - cytology; Gene Expression Regulation; Histone Deacetylase Inhibitors - chemistry; Histone deacetylases (HDACs); Histone Deacetylases - metabolism; Histones - chemistry; Inflammation; Macrophages; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Phenotype; Tibia - metabolism; Epigenetics; Chromatin modifying enzymes (CME); Inflammation; Macrophages; Atherosclerosis; Histone deacetylases (HDACs)
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.11.029

•HMTs and HDACs regulate M1, M2 and Mox polarization.•HDAC inhibitors increase Abca1 and Abcg1 expression and histone acetylation.•HDAC inhibition modifies macrophage metabolism and protects against apoptosis.•Blocking HDAC3 activity improves atherogenic macrophage activities. Macrophages determine the outcome of atherosclerosis by propagating inflammatory responses, foam cell formation and eventually necrotic core development. Yet, the pathways that regulate their atherogenic functions remain ill-defined. It is now apparent that chromatin remodeling chromatin modifying enzymes (CME) governs immune responses but it remains unclear to what extent they control atherogenic macrophage functions. We hypothesized that epigenetic mechanisms regulate atherogenic macrophage functions, thereby determining the outcome of atherosclerosis. Therefore, we designed a quantitative semi-high-throughput screening platform and studied whether the inhibition of CME can be applied to improve atherogenic macrophage activities. We found that broad spectrum inhibition of histone deacetylases (HDACs) and histone methyltransferases (HMT) has both pro- and anti-inflammatory effects. The inhibition of HDACs increased histone acetylation and gene expression of the cholesterol efflux regulators ATP-binding cassette transporters ABCA1 and ABCG1, but left foam cell formation unaffected. HDAC inhibition altered macrophage metabolism towards enhanced glycolysis and oxidative phosphorylation and resulted in protection against apoptosis. Finally, we applied inhibitors against specific HDACs and found that HDAC3 inhibition phenocopies the atheroprotective effects of pan-HDAC inhibitors. Based on our data, we propose the inhibition of HDACs, and in particular HDAC3, in macrophages as a novel potential target to treat atherosclerosis.