Reactive oxygen species-driven HIF1α triggers accelerated glycolysis in endothelial cells exposed to low oxygen tension.
Endothelial cells and their metabolic state regulate glucose transport into underlying tissues. Here, we show that low oxygen tension stimulates human umbilical vein endothelial cell18F-fluorodeoxyglucose (18F-FDG) uptake and lactate production. This was accompanied by augmented hexokinase activity and membrane Glut-1, and increased accumulation of hypoxia-inducible factor-1α (HIF1α). Restoration of oxygen reversed the metabolic effect, but this was blocked by HIF1α stabilization. Hypoxia-stimulated18F-FDG uptake was completely abrogated by silencing of HIF1α expression or by a specific inhibitor. There was a rapid and marked increase of reactive oxygen species (ROS) by hypoxia, and ROS scavenging or NADPH oxidase inhibition completely abolished hypoxia-stimulated HIF1α and18F-FDG accumulation, placing ROS production upstream of HIF1α signaling. Hypoxia-stimulated HIF1α and18F-FDG accumulation was blocked by the protein kinase C (PKC) inhibitor, staurosporine. The phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, blocked hypoxia-stimulated18F-FDG uptake and attenuated hypoxia-responsive element binding of HIF1α without influencing its accumulation. Thus, ROS-driven HIF1α accumulation, along with PKC and PI3K signaling, play a key role in triggering accelerated glycolysis in endothelial cells under hypoxia, thereby contributing to18F-FDG transport.
Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea.
Jin-Young
JY
Paik
Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Kyung-Ho
KH
Jung
Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Jin-Hee
JH
Lee
Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Jin-Won
JW
Park
Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: khnm.lee@samsung.com.
Kyung-Han
KH
Lee
D001692:Biological Transport; D015687:Cell Hypoxia; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D019788:Fluorodeoxyglucose F18; D019869:Phosphatidylinositol 3-Kinases; D006593:Hexokinase; D011493:Protein Kinase C
(18)F–FDG; Endothelial cell; Glycolysis; HIF1α; Hypoxia; ROS