Nitric oxide stimulates 18F-FDG uptake in human endothelial cells through increased hexokinase activity and GLUT1 expression.
The endothelium constitutes a functionally active organ critically involved in angiogenesis. Nitric oxide (NO) is an important regulator of vascular homeostasis and angiogenesis and stimulates glucose metabolism in certain cells. We thus investigated the effect of exogenous NO on (18)F-FDG transport in human endothelial cells.


METHODS
Human umbilical vein endothelial cells (HUVECs) were treated with the NO donors sodium nitroprusside (SNP) or diethylenetriamine (DETA), in concentrations of 1 micromol/L-1 mmol/L for up to 24 h. (18)F-FDG uptake levels corrected for protein content were determined by cellular radioactivity measured after 30-min incubation. Cells were evaluated for total hexokinase activity and plasma membrane glucose transporter 1 (GLUT1) levels, and involvement of potential signaling pathways was investigated by cotreatment with respective protein kinase inhibitors.


RESULTS
Both SNP and DETA stimulated HUVEC (18)F-FDG uptake, which began at 16 h and peaked at 24 h. The increase in (18)F-FDG uptake was dose dependent, reaching 464.0% +/- 49.8% and 254.5% +/- 10.8% of control levels at 24 h with 1 mmol/L SNP and DETA, respectively. Exposure of HUVECs to 1 mmol/L SNP resulted in a 3.5 +/- 0.3-fold elevation in hexokinase activity (P < 0.01) and a significant increase in GLUT1 levels. SNP-stimulated (18)F-FDG uptake was abolished by cotreatment with cycloheximide, the tyrosine kinase inhibitor genistein, the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin, or the protein kinase C inhibitor staurosporine.


CONCLUSIONS
NO stimulates (18)F-FDG uptake in HUVECs through an increase in GLUT1 expression and hexokinase activity, which appears to involve both protein kinase C and PI3K pathways.
Paik
Jin-Young
JY
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Lee
Kyung-Han
KH
Ko
Bong-Ho
BH
Choe
Yearn Seong
YS
Choi
Yong
Y
Kim
Byung-Tae
BT
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D020030:Nitric Oxide Donors; D011073:Polyamines; D019275:Radiopharmaceuticals; C495677:SLC2A1 protein, human; C005391:diethylenetriamine; D019788:Fluorodeoxyglucose F18; D009599:Nitroprusside; D009569:Nitric Oxide; D006593:Hexokinase