PT  - JOURNAL ARTICLE
AU  - Su Jin Lee
AU  - Cung Hoa Thien Quach
AU  - Kyung-Ho Jung
AU  - Jin-Young Paik
AU  - Jin Hee Lee
AU  - Jin Won Park
AU  - Kyung-Han Lee
TI  - Oxidized Low-Density Lipoprotein Stimulates Macrophage <sup>18</sup>F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation
AID  - 10.2967/jnumed.114.139428
DP  - 2014 Oct 01
TA  - Journal of Nuclear Medicine
PG  - 1699--1705
VI  - 55
IP  - 10
4099  - http://jnm.snmjournals.org/content/55/10/1699.short
4100  - http://jnm.snmjournals.org/content/55/10/1699.full
SO  - J Nucl Med2014 Oct 01; 55
AB  - For 18F-FDG PET to be widely used to monitor atherosclerosis progression and therapeutic response, it is crucial to better understand how macrophage glucose metabolism is influenced by the atherosclerotic microenvironment and to elucidate the molecular mechanisms of this response. Oxidized low-density lipoprotein (oxLDL) is a key player in atherosclerotic inflammation that promotes macrophage recruitment, activation, and foam cell formation. We thus explored the effect of oxLDL on macrophage 18F-FDG uptake and investigated the underlying molecular mechanism including the roles of hypoxia-inducible factor-1α (HIF-1α) and reactive oxygen species (ROS). Methods: RAW264.7 macrophages were stimulated with native LDL, oxLDL, or lipopolysaccharide. Cells were assessed for 18F-FDG uptake, lactate production, membrane glucose transporter 1 (GLUT1) expression, and hexokinase activity. ROS generation, Nox expression, and HIF-1α activity were also measured. Results: oxLDL (20 μg/mL) induced a 17.5 ± 1.7-fold increase in macrophage 18F-FDG uptake by 24 h, which was accompanied by increased lactate production, membrane GLUT1 expression, and hexokinase activity. oxLDL-stimulated 18F-FDG uptake was completely blocked by inhibitors of Src or phosphoinositide 3-kinase. ROS generation was increased to 262.4% ± 17.9% of controls by oxLDL, and N-acetyl-l-cysteine completely abrogated both oxLDL-induced ROS production and 18F-FDG uptake. oxLDL increased Nox2 expression, and nicotinamide adenine dinucleotide phosphate oxidase inhibition totally blocked increased ROS generation and 18F-FDG uptake by oxLDL. Finally, there was a clear ROS-dependent increase of HIF-1α accumulation by oxLDL, and silencing of HIF-1α completely abolished the metabolic effect of oxLDL. Conclusion: oxLDL is a strong stimulator of macrophage 18F-FDG uptake and glycolysis through upregulation of GLUT1 and hexokinase. This metabolic response is mediated by Nox2-dependent ROS generation that promotes HIF-1α activation.