Monocyte subsets in coronary artery disease and their associations with markers of inflammation and fibrinolysis
Introduction
Monocyte-derived ‘foam’ cells have been established as a hallmark and key pathogenic feature of atherosclerosis, a disease of inflammatory aetiology [1], [2], [3]. High total monocyte count is a strong predictor of high risk of coronary artery disease (CAD) or myocardial infarction (MI) [4]. However the roles of monocytes in atherosclerosis are diverse, including involvement in inflammatory responses and the regulation of thrombogenic status (e.g., via tissue factor expression and modulation of fibrinolysis). Indeed, monocytes have also been implicated in physiologically beneficial processes related to scavenging of redundant/pathological material, angiogenesis and repair [5], [6], [7].
This diversity of monocyte functions can be partly attributed to the existence of different monocyte subsets distinguished by specific phenotypic and functional properties [8], [9], [10], [11], [12], [13]. Specific monocyte subsets are differentially involved in the pathogenesis and outcome of acute coronary syndromes, heart failure, and stroke, amongst other conditions [14], [15]. However, most previous studies in both rodents and humans are limited by the analysis of monocytes as only two subsets, where CD16+ cells are considered as a single population, in contract to the current monocyte nomenclature.
The aim of this study was to provide a detailed phenotypic comparison of the three human monocyte subsets defined according to contemporary nomenclature between patients with CAD and healthy subjects, with a focus on investigating differences in expression of receptors involved in inflammatory and reparative responses between subsets. Additionally, we provide an insight into monocyte functional status, by measuring intracellular IKKβ (IκB kinase β, a marker of activation of nuclear factor κB [NFκB] pathway), quantify monocyte interactions with platelets, and evaluate association of monocyte characteristics with plasma markers of inflammation and fibrinolysis.
Section snippets
Methods
We recruited 53 patients with stable CAD confirmed during elective coronary angiography on contemporary medical therapy with no hospital admissions for ≥3 months and free from angina at the time of study (referred to Sandwell and West Birmingham Hospitals NHS Trust). Exclusion criteria comprised factors known to affect monocyte count (infectious disease, inflammatory disorders and their treatment, cancer, haemodynamically significant valvular heart disease, atrial fibrillation, renal failure
Results
The study groups were well matched for age, sex, body mass index, and blood pressure; however, the healthy subjects had fewer smokers (Table 1). Among patients with CAD, 28 (53%) had a history of hypertension, 9 (17%) had diabetes mellitus, and 24 (46%) had a history of previous myocardial infarction. The CAD patients received the following pharmacological treatment: aspirin 46 (87%), clopidogrel 23 (43%), prasugrel 2 (4%), statins 47 (89%), angiotensin converting enzyme inhibitors 41 (77%),
Discussion
This study describes the presence of significant changes in human monocyte phenotype in subjects with CAD, attributable to specific monocyte subsets. We show for the first time, significant up-regulation of IL6R on Mon1 and Mon2 subsets. Second, we show a significant up-regulation of CXCR4 expression on Mon3, with a similar trend for Mon2. Third, we also show a significant increase in CD34 expression on all monocyte subsets.
In a recently published meta-analysis, Sarwar et al. provided
Conclusions
There are significant differences in monocyte phenotype in CAD, which are differentially attributable to the three monocyte subsets defined according to contemporary nomenclature. These findings add to the emerging data implicating specific roles for Mon2 monocytes in the pathogenesis of atherosclerosis.
Addendum on authors' contributions
E Shantsila: concept and design, data collection, analysis and/or interpretation of data; LD Tapp: data collection, critical revising the intellectual content; BJ Wrigley: data collection, critical revising the intellectual content; B Pamukcu: data collection, critical revising the intellectual content; S Apostolakis: in vitro experiments, critical revising the intellectual content; S Montoro-García: data collection, critical revising the intellectual content; GYH Lip: concept and design,
Funding
This work was supported by the Heart Research UK [grant number RG 2579/09/10].
Conflict of interest
None declared.
Acknowledgements
None.
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