Abstract
Objective: Inflammation and immunity activation play a key role in atherosclerosis (ATS) onset and progression. Aim of this study was to investigate the relationships between phenotype of circulating monocytes and coronary artery disease (CAD) development in a histologically well-characterized swine model of ATS. Methods: Blood samples were obtained from 6 animals at baseline and after 16 weeks high fat cholesterolenriched diet. Flow cytometry monocyte identification was performed (CD172a marker). Adhesion (CD18a, CD11a, CD11R3, CD49d, CD29), differentiation (CD14) and activation receptors (SLA-DR, CD16, CD163) were quantified as percentage of positivity (%) and Relative Fluorescence Intensity (RFI). Lipid parameters (LDL, oxLDL, HDL) and soluble endothelial ICAM-1 were measured and histologic quantitative assessment of coronary ATS was performed. Results: Flow cytometry analysis demonstrated a significant post-diet decrease of CD14 RFI and an increment of % SLA-DR. Pre-diet values of ICAM-1 and % SLA-DR correlated reciprocally (P=0.0191) and with several CAD severity indexes (P≤0.02). Positive correlations between RFI changes of CD29 (P=0.0213) and CD18a (P=0.0341) and morphometric indexes of coronary ATS were found. Post-diet RFI values of CD29, CD18a and CD16 were also closely related to morphometric parameters (P<0.03). A cumulative post-diet tendency to increase of CD14low/ CD163high monocyte fraction (45.07 ± 2.27 vs. 40.14 ± 3.16) and a tight correlation between changes of this monocyte subset and corresponding HDL variations (P=0.0100) were also observed. Conclusions: Blood monocyte orientation towards a macrophage-like phenotype, similar to a HDL-induced maturation, and a close association between markers changes and severity of diet induced coronary ATS could provide new insights into plaque growth and progression in CAD.
Highlights
Atherosclerosis (ATS) is a chronic inflammatory process of large and medium-size arteries, in which the focal endothelial activation, induced by hypercholesterolemia and lipoproteins deposition in the arterial intima, represents an essential initiating event [1,2]
hypercholesterolemic diet (HCD)-treated pigs exhibited a slight post-diet decrease of total white blood cells (WBCs) count and hematocrit volume compared with baseline values
In the present study we employed a swine model of coronary artery disease (CAD) in order to evaluate, by flow cytometry, HCD-induced phenotype modifications of circulating monocytes and their relationship with severity and extent of atherosclerotic lesions assessed by histomorphomety
Summary
Atherosclerosis (ATS) is a chronic inflammatory process of large and medium-size arteries, in which the focal endothelial activation, induced by hypercholesterolemia and lipoproteins deposition in the arterial intima, represents an essential initiating event [1,2]. The endothelial activation determines an increased adhesion molecule expression and chemokine production, which mediate the initial rolling of blood leukocytes on the endothelial vascular surface, their subsequent firm adhesion at activation sites, and their final recruitment into the underlying intima [3,4]. Hemodynamic flow patterns, typical of ATS-prone segments (low or oscillatory shear stress), give rise to an increased expression of adhesion molecule and inflammatory genes by endothelial cells and, together with lipoprotein accumulation, aggravate intimal inflammation [5]. Immunohistochemical analysis of human atherosclerotic lesions, as well as experimental studies in gene-targeted mice, suggested that the monocyte integrins VLA-4 (very late antigen-4) and LFA-1 (lymphocyte function-associated antigen-1) and their corresponding endothelial cell ligands, VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1), are important in plaque initiation [7].
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