Clinical Research
Cardiac Imaging
Hypoxia But Not Inflammation Augments Glucose Uptake in Human Macrophages: Implications for Imaging Atherosclerosis With 18Fluorine-Labeled 2-Deoxy-D-Glucose Positron Emission Tomography

https://doi.org/10.1016/j.jacc.2011.03.044Get rights and content
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Objectives

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 18fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically.

Background

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.

Methods

We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake.

Results

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.

Conclusions

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.

Key Words

atherosclerosis
fluorodeoxyglucose
glucose transporter
hexokinase
hypoxia
inflammation
positron emission tomography
statin
2-deoxy-D-glucose

Abbreviations and Acronyms

acLDL
acetylated low-density lipoprotein
EC
endothelial cell
FdG
18fluorine-labeled 2-deoxy-D-glucose
GLUT
glucose transporter
HIF
hypoxia-inducible factor
HK
hexokinase
HLA
human leukocyte antigen
IFN
interferon
LDL
low-density lipoprotein
mRNA
messenger ribonucleic acid
PET
positron emission tomography
RNA
ribonucleic acid
RT-qPCR
reverse transcription–quantitative polymerase chain reaction
siRNA
small interfering ribonucleic acid
SMC
smooth muscle cell
TNF
tumor necrosis factor
2dG
2-deoxy-D-glucose

Cited by (0)

Financial support for this project was provided by the Donald W. Reynolds Foundation (Las Vegas, NV). Dr. Christen is an employee of Boston Scientific. All other authors have reported that they have no relationships to disclose. Drs. Folco and Sheikine contributed equally to this work.