Regulatory mechanisms of monocytes and macrophages in atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease is a leading cause of mortality. Given the importance of monocytes and macrophages in all stages of atherosclerotic development and progression, understanding their regulatory mechanisms can inform the development of future immune-modulating therapies for atherosclerosis. The overall aim of this thesis was to identify novel regulators of macrophage activation, including epigenetic regulators, in the context of atherosclerotic cardiovascular diseases. In the first part of this thesis, we investigate the epigenetic modulation of macrophages. These chapters focus on the immunomodulatory properties of the polycomb repressive complex 2 (PRC2) and its subunits, which deposit the repressive histone mark H3K27me3, as well as the role of another epigenetic regulator, HDAC3. In the second part of this thesis, we examine how the exposome regulates monocyte activation in clinical settings of atherosclerotic cardiovascular disease. In a clinical observational study, we explored a potential molecular mechanism underlying monocyte inflammation in patients with and without atherosclerotic cardiovascular disease and with or without high plasma Lp(a) levels. In a randomized crossover intervention study, we investigated the effects of intermittent fasting in individuals with metabolic syndrome. Together, these studies provide new insights into the complex regulation of macrophage activation in ASCVD.