Abstract
Atherosclerotic cardiovascular disease (CVD) is a lipid-driven chronic inflammatory disease, in which macrophages are responsible for taking up these lipids and driving disease progression. Over the years, we and others have uncovered key pathways that regulate macrophage number/function and identified how metabolic disorders such as diabetes and obesity, which are common risk factors for CVD, exacerbate these pathways. This ultimately accelerates the progression of atherosclerosis and hinders atherosclerotic regression. In this review, we discuss the different types of macrophages, from monocyte-derived macrophages, local macrophage proliferation, to macrophage-like vascular smooth muscle cells, that contribute to atherosclerosis as well as myeloid-derived suppressor cells that may have anti-atherogenic effects. We will also discuss how diabetes and obesity influence plaque macrophage accumulation and monocyte production (myelopoiesis) to promote atherogenesis as well as an exciting therapeutic target, S100A8/A9, which mediates myelopoiesis in response to both diabetes and obesity, shown to be effective in reducing atherosclerosis in pre-clinical models of diabetes.
Highlights
Cardiovascular disease (CVD) remains the leading cause of death worldwide and is of major concern in populations with increasing prevalence of metabolic disease (World Health Organization, 2017)
Diabetes and obesity are associated with exacerbated macrophage inflammation, which contributes to an overall increase in cardiovascular risk
Macrophages play a crucial role in the development of CVD by promoting atherosclerosis and contribute to plaque vulnerability
Summary
Cardiovascular disease (CVD) remains the leading cause of death worldwide and is of major concern in populations with increasing prevalence of metabolic disease (World Health Organization, 2017). Diabetes and obesity are both independent risk factors for CVD, with diabetic and pre-diabetic patients accounting for 65% of all CVD deaths (Barr et al, 2007; Flint et al, 2010). In recent years, targeting inflammation in CVD with the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) demonstrated that inhibiting interleukin-1β (IL-1β) reduces the incidence of secondary cardiovascular events, independent of lipid lowering (Ridker et al, 2017). It has become well established through pre-clinical models that changes in the inflammatory milieu of atherosclerotic plaques, as well as systemic inflammation, play an important role in the development and vulnerability of atherosclerotic plaques to rupture. Myelopoiesis in Metabolic Disease and Atherosclerosis role of different sources of macrophages in atherosclerosis in the context of diabetes and obesity with a focus on the role of monocyte-derived macrophages and myelopoiesis in promoting atherosclerosis
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