Hypoxia But Not Inflammation Augments Glucose Uptake in Human Macrophages Implications for Imaging Atherosclerosis With (18)Fluorine-Labeled 2-Deoxy-D-Glucose Positron Emission Tomography
ABSTRACT This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the (18)fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically.
Patient studies suggest that positron emission tomography (PET) using FdG can detect "active" atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown.
We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake.
Hypoxia, but not pro-inflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells. Statins attenuated this process in vitro, suggesting that these agents have a direct effect on human macrophages. Immunohistochemical study of human plaques revealed abundant expression of proteins regulating glucose utilization, predominantly in macrophage-rich regions of the plaques-regions previously proved hypoxic. Smooth-muscle cells and endothelial cells markedly increased rates of glucose uptake when exposed to pro-inflammatory cytokines.
Glucose uptake and, probably, FdG uptake signals in atheroma may reflect hypoxia-stimulated macrophages rather than mere inflammatory burden. Cytokine-activated smooth-muscle cells also may contribute to the FdG signal.
SourceAvailable from: María Fernández-VelascoJournal of the American College of Cardiology 03/2013; 61(10). DOI:10.1016/S0735-1097(13)61153-5 · 15.34 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Although it is accepted that macrophage glycolysis is upregulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage proinflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque. We studied the interplay between macrophage energy metabolism, polarization, and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed. We observed that macrophage energetics and inflammatory activation are closely and linearly related, resulting in dynamic calibration of glycolysis to keep pace with inflammatory activity. In addition, we show that macrophage glycolysis and proinflammatory activation mainly depend on hypoxia-inducible factor and on its impact on glucose uptake, and on the expression of hexokinase II and ubiquitous 6-phosphofructo-2-kinase. As a consequence, hypoxia potentiates inflammation and glycolysis mainly via these pathways. Moreover, when macrophages' ability to increase glycolysis through 6-phosphofructo-2-kinase is experimentally attenuated, cell viability is reduced if subjected to proinflammatory or hypoxic conditions, but unaffected under control conditions. In addition to this, granulocyte-macrophage colony-stimulating factor enhances anerobic glycolysis while exerting a mild proinflammatory activation. These findings, in human and murine cells and in an animal model, show that hypoxia potentiates macrophage glycolytic flux in concert with a proportional upregulation of proinflammatory activity, in a manner that is dependent on both hypoxia-inducible factor -1α and 6-phosphofructo-2-kinase. © 2015 American Heart Association, Inc.Arteriosclerosis Thrombosis and Vascular Biology 04/2015; DOI:10.1161/ATVBAHA.115.305551 · 5.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Abstract Purpose The human arterial wall is smaller than the spatial resolution of current positron emission tomographs. Therefore, partial volume effects should be considered when quantifying arterial wall 18F-FDG uptake. We evaluated the impact of a novel method for partial volume effect (PVE) correction with contrast-enhanced CT (CECT) assistance on quantification of arterial wall 18F-FDG uptake at different imaging time-points. Methods Ten subjects were assessed by CECT imaging and dual time-point PET/CT imaging at approximately 60 and 180 min after 18F-FDG administration. For both time-points, uptake of 18F-FDG was determined in the aortic wall by calculating the blood pool-corrected maximum standardized uptake value (cSUVMAX) and cSUVMEAN. The PVE-corrected SUVMEAN (pvcSUVMEAN) was also calculated using 18F-FDG PET/CT and CECT images. Finally, corresponding target-to-background ratios (TBR) were calculated. Results At 60 min, pvcSUVMEAN was on average 3.1 times greater than cSUVMAX (P < .0001) and 8.5 times greater than cSUVMEAN (P < .0001). At 180 min, pvcSUVMEAN was on average 2.6 times greater than cSUVMAX (P < .0001) and 6.6 times greater than cSUVMEAN (P < .0001). Conclusion This study demonstrated that CECT-assisted PVE correction significantly influences quantification of arterial wall 18F-FDG uptake. Therefore, partial volume effects should be considered when quantifying arterial wall 18F-FDG uptake with PET.European journal of nuclear medicine and molecular imaging 05/2015; · 5.22 Impact Factor