Macrophage regulatory mechanisms in atherosclerosis: The interplay of lipids and inflammation

Research output: PhD ThesisPhd-Thesis - Research and graduation internal

Abstract

Atherosclerosis is a lipid driven chronic inflammatory disorder of the arteries. Monocytes, macrophages and foam cells are the central players in atherosclerosis and contribute to all stages of lesion formation. Skewing monocytes and macrophages to cells with anti-atherogenic properties could be envisaged as an athero-protective treatment. The overall aim of this thesis was to identify novel regulators in monocytes and macrophages to combat atherosclerosis. Epigenetic pathways have been identified to play a key role in monocyte-to-macrophage differentiation and activation. We hypothesized that interference with these pathways in macrophages can improve atherosclerosis outcome. In this thesis we validated the role of the repressive H3K27me3 methyltransferase enhancer of the zeste homolog 2 (Ezh2) and lysine demethylase 6b (Kdm6b) in macrophage foam cells and atherosclerotic lesion development in mice. We identified the H3K27me3 methyltransferase Ezh2 as a novel target in myeloid cells to combat atherosclerosis. In addition to histone modifications, we highlight that also DNA methylation is an important regulator in human monocyte-to-macrophage differentiation. Lastly, we studied the link between LDL and monocyte activation, two key players in atherosclerosis. By use of PCSK9 monoclonal antibodies we showed that LDL lowering itself contributes to anti-inflammatory effects on monocytes.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Supervisors/Advisors
  • de Winther, Menno, Supervisor
  • Lutgens, E., Supervisor
  • Gijbels, Maria, Co-supervisor
  • Van den Bossche, Jan, Co-supervisor
Award date19 Jan 2018
Print ISBNs9789402808773
Publication statusPublished - 2018

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