t0901317 and 2-fluoro-2-deoxyglucose-6-phosphate

(18)F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging of atherosclerosis in the clinic is based on preferential accumulation of radioactive glucose analog in atherosclerotic plaques. FDG-PET is challenging in mouse models due to limited resolution and high cost. We aimed to quantify accumulation of nonradioactive glucose metabolite, FDG-6-phosphate, in the mouse atherosclerotic plaques as a simple alternative to PET imaging.. Nonradioactive FDG was injected 30 minutes before euthanasia. Arteries were dissected, and lipids were extracted. The arteries were re-extracted with 50% acetonitrile-50% methanol-0.1% formic acid. A daughter ion of FDG-6-phosphate was quantified using liquid chromatography and mass spectrometry (LC/MS/MS). Thus, both traditional (cholesterol) and novel (FDG-6-phosphate) markers were assayed in the same tissue. FDG-6-phosphate was accumulated in atherosclerotic lesions associated with carotid ligation of the Western diet fed ApoE knockout mice (5.9 times increase compare to unligated carotids, p<0.001). Treatment with the liver X receptor agonist T0901317 significantly (2.1 times, p<0.01) reduced FDG-6-phosphate accumulation 2 weeks after surgery. Anti-atherosclerotic effects were independently confirmed by reduction in lesion size, macrophage number, cholesterol ester accumulation, and macrophage proteolytic activity.. Mass spectrometry of FDG-6-phosphate in experimental atherosclerosis is consistent with plaque inflammation and provides potential translational link to the clinical studies utilizing FDG-PET imaging.

Topics: Animals; Apolipoproteins E; Arteries; Atherosclerosis; Carotid Arteries; Cell Line; Chemistry, Pharmaceutical; Cholesterol; Chromatography, Liquid; Diagnostic Imaging; Disease Models, Animal; Drug Design; Glucose; Glucose-6-Phosphate; Humans; Hydrocarbons, Fluorinated; Ions; Liver X Receptors; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Orphan Nuclear Receptors; Plaque, Atherosclerotic; Positron-Emission Tomography; Sulfonamides; Time Factors