Abstract
Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.
Highlights
Atherosclerotic cardiovascular disease (CVD), including myocardial infarction and stroke, is the leading cause of death worldwide
In the current paper we add an important dimension to this pathophysiological framework by showing for the first time that inflammatory reprogramming of innate immune cells in Medicine colonies /10^3 mononuclear cells (MNCs) colonies /10^3 MNCs colonies /10^3 MNCs
In patients with chronic coronary artery disease (CAD) due to severe coronary atherosclerosis, isolated bone marrow mononuclear cells showed a higher cytokine production capacity and increased metabolic rate compared to individuals without coronary atherosclerosis
Summary
Atherosclerotic cardiovascular disease (CVD), including myocardial infarction and stroke, is the leading cause of death worldwide. Western-type diet feeding of low-density lipoprotein receptor deficient (Ldlr-/-) mice induces inflammatory activation of monocytes by epigenetic reprogramming of HSPCs which persists in normocholesterolemic conditions (Christ et al, 2018) This resembles the finding of persistent functional and transcriptional hyperresponsive monocytes in patients with dyslipidemia despite cholesterol-lowering treatment (Bekkering et al, 2019). Flow cytometry and RNAseq analysis revealed inflammatory transcriptional reprogramming and myeloid skewing These results show that in patients with atherosclerosis, activation of the innate immune system occurs at the level of bone marrow myeloid progenitors, which adds exciting opportunities for novel treatment strategies
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