Inhibiting epigenetic enzymes to improve atherogenic macrophage functions

Jan Van Den Bossche*, Annette E. Neele, Marten A. Hoeksema, Femke De Heij, Marieke C.S. Boshuizen, Saskia Van Der Velden, Vincent C. De Boer, Kris A. Reedquist, Menno P.J. De Winther

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)396-402
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume455
Issue number3-4
DOIs
Publication statusPublished - 12 Dec 2014

Cite this

Van Den Bossche, J., Neele, A. E., Hoeksema, M. A., De Heij, F., Boshuizen, M. C. S., Van Der Velden, S., ... De Winther, M. P. J. (2014). Inhibiting epigenetic enzymes to improve atherogenic macrophage functions. Biochemical and Biophysical Research Communications, 455(3-4), 396-402. https://doi.org/10.1016/j.bbrc.2014.11.029