Glucose Metabolic Trapping in Mouse Arteries: Nonradioactive Assay of Atherosclerotic Plaque Inflammation Applicable to Drug Discovery

• Published in: PloS one Vol. 7; no. 11; p. e50349
• Main Authors: Conway, Richard G., Chernet, Eyassu, De Rosa, David C., Benschop, Robert J., Need, Anne B., Collins, Emily C., Bean, James S., Kalbfleisch, J. Michael, Rekhter, Mark D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.11.2012; Public Library of Science (PLoS)
• Subjects: Accumulation; Acetonitrile; Animal models; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Arteries; Arteries - metabolism; Arteriosclerosis; Atherosclerosis; Atherosclerosis - therapy; Bioaccumulation; Biology; Cardiology; Carotid Arteries - metabolism; Cell Line; Chemistry, Pharmaceutical - methods; Cholesterol; Cholesterol - metabolism; Chromatography; Chromatography, Liquid - methods; Diabetes; Diagnostic Imaging - methods; Disease Models, Animal; Drug Design; Drug discovery; Euthanasia; Formic acid; Gene expression; Glucose; Glucose - analogs & derivatives; Glucose - metabolism; Glucose-6-Phosphate - analogs & derivatives; Glucose-6-Phosphate - metabolism; Humans; Hydrocarbons, Fluorinated - pharmacology; Hypotheses; Hypoxia; Imaging; Inflammation; Ions; Laboratories; Lesions; Lipids; Liquid chromatography; Liver; Liver X Receptors; Macrophages; Mass spectrometry; Mass Spectrometry - methods; Mass spectroscopy; Medical imaging; Medicine; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear medicine; Organic compounds; Orphan Nuclear Receptors - antagonists & inhibitors; Phosphate; Phosphates; Plaque, Atherosclerotic - metabolism; Plaques; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Proteolysis; R&D; Research & development; Rodents; Scientific imaging; Spectroscopy; Sulfonamides - pharmacology; Surgery; Time Factors; Tomography; Veins & arteries; Indiana; United States > US; Indianapolis Indiana
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0050349

(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.