title: Glucose metabolic trapping in mouse arteries: nonradioactive assay of atherosclerotic plaque inflammation applicable to drug discovery.
abstract: BACKGROUND
  (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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiometabolic Diseases and Diabetic Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Conway
authors.forename: Eyassu
authors.initials: E
authors.lastname: Chernet
authors.forename: David C
authors.initials: DC
authors.lastname: De Rosa
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Benschop
authors.forename: Anne B
authors.initials: AB
authors.lastname: Need
authors.forename: Emily C
authors.initials: EC
authors.lastname: Collins
authors.forename: James S
authors.initials: JS
authors.lastname: Bean
authors.forename: J Michael
authors.initials: JM
authors.lastname: Kalbfleisch
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rekhter
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001158:Arteries / Q000378:metabolism*; D050197:Atherosclerosis / Q000628:therapy; D002339:Carotid Arteries / Q000378:metabolism; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002784:Cholesterol / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D003952:Diagnostic Imaging / Q000379:methods; D004195:Disease Models, Animal; D015195:Drug Design; D005947:Glucose / Q000031:analogs & derivatives / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007477:Ions; D000071518:Liver X Receptors; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001057:Apolipoproteins E; D002784:Cholesterol; D005947:Glucose; D019298:Glucose-6-Phosphate; D006845:Hydrocarbons, Fluorinated; D007477:Ions; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C047515:2-fluoro-2-deoxyglucose-6-phosphate