Circulating monocytes and atherogenesis: From animal experiments to human studies

Abstract

Despite significant improvements in the prevention and management of atherosclerosis, its consequences still remain a major cause of disability and mortality. Better understanding of pathophysiological processes implicated in the initial stages of atherogenesis is critical for the discovery of effective approaches to prevent ischaemic stage of the disease and to reduce huge economic and social burden currently associated with atherosclerosis (1). According to the current paradigm the atherosclerotic process is primarily initiated in the vascular wall itself where monocyte-derived macrophages transform to ‘foam’ cells by accumulating lipids (2). Consequent apoptosis or death of macrophages is largely responsible for necrotic core generation, progressive accumulation of free cholesterol and expansion of the necrotic core within plaques. Often, unbalanced generation of inflammatory cytokines by plaque monocyte-derived macrophages (e.g. via up-regulation of Toll-like receptors) as well as angiogenic promoting pathological plaque neovascularisation, and enzymes degrading extracellular matrix results in destabilisation of atherosclerotic plaques (3–5). Whilst a critical role of vascular wall monocyte-derived macrophages in atherosclerotic plaque formation is widely recognised, the impact of circulating monocytes on atherogenesis is less established. For example, accumulation of modified (mainly oxidised) lipids via scavenger receptors was, until recently, exclusively attributed to vascular wall resident macrophages rather than circulating monocytes (6). Oxidised low-density lipoproteins (LDL) taken up via scavenger receptors (e.g. CD36 and CD204) are delivered to lysosomes, where they undergo esterification by cholesterol esterase and are largely converted into free cholesterol and fatty acids (6). It has been reported that CD36 contributes 60–70% of cholesterol ester accumulation in macrophages exposed to oxidised LDL (7). Deletion of the genes encoding CD36 and CD204 retards the development of atherosclerotic lesions in animal models of atherosclerosis (6). However, circulating monocytes are equipped with these same scavenger receptors and may thus start accumulating lipids even prior to their migration to tissues and differentiation to macrophages (8). Exposure to modified LDL induces rapid ‘foam’ cell formation from freshly isolated peripheral blood monocytes, accompanied by upregulation of CD204 and CD36 (8). The clinical relevance of these findings is supported by the observation that an absence of CD36 on circulating monocytes in individuals from a Japanese population results in 40–50% reduction in oxidised LDL binding to monocyte-derived-macrophages compared to normal subjects (9). Certainly, monocyte counts are increased in patients with stenotic coronary artery disease and the Intermountain Heart Collaborative Study Group recently reported a population of 3,227 patients with or without coronary artery disease whereby high monocyte counts were independent predictors of future myocardial infarction and death (10). However, the impact of monocytes in atherogenesis may go far beyond direct lipid accumulation as they are also actively involved in inflammatory responses attributable to their principal function within the innate immune system. Indeed, Correspondence to: Dr. Eduard Shantsila University of Birmingham Centre for Cardiovascular Sciences, City Hospital Birmingham, B18 7QH, UK Tel: +44 121 554 3801, Fax: +44 121 554 4083 E-mail: e.shantsila@bham.ac.uk