title: Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a (99m)Tc-labeled dual-domain cytokine ligand.
abstract: Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) play a critical role in initiating and accelerating atherosclerosis. This study evaluated the imaging properties of (99m)Tc-TNFR2-Fc-IL-1RA ((99m)Tc-TFI), a dual-domain cytokine radioligand that targets TNF-α and IL-1β pathways, in assessing atherosclerosis development in apolipoprotein-E-deficient (ApoE(-)(/)(-)) mice.
  
  
  METHODS
  The feasibility and specificity of detecting atherosclerosis with (99m)Tc-TFI SPECT imaging were investigated in ApoE(-)(/)(-) and ApoE(+)(/)(+) mice. Fifty-four ApoE(-)(/)(-) mice were fed either an atherogenic diet (AGD) or a normal diet (ND) beginning at 5 weeks of age. Eighteen Apo-E wild-type (ApoE(+)(/)(+)) mice were fed an ND. Two groups of ApoE(-)(/)(-) mice (n=12 each group) on AGD and ND were imaged three times with (99m)Tc-TFI and a high-resolution SPECT system at 20-25, 30-40, and 48-52 weeks to study the evolution of atherosclerotic plaque.
  
  
  RESULTS
  Focal radioactive accumulations in the aortic arch region were observed in the ApoE(-)(/)(-) mice (n=12) on AGD but not in the ApoE(+)(/)(+) mice on ND (n=10). Apo-E(-)(/)(-) mice on ND (n=11) exhibited lower radioactive uptake than ApoE(-)(/)(-) mice on AGD (P<0.05). Co-injection of an excess of cold ligand with (99m)Tc-TFI resulted in significant reduction of (99m)Tc-TFI uptake in the ApoE(-)(/)(-) mice on AGD. Longitudinal studies showed that (99m)Tc-TFI uptake in the aortas of ApoE(-)(/)(-) mice progressively increased from 20 to 48 weeks. Real-time PCR assays demonstrated that atherosclerotic aortas expressed significantly higher IL-1β and TNF-α than the aortas from wild-type controls.
  
  
  CONCLUSIONS
  Atherosclerotic plaques were detected by (99m)Tc-TFI imaging in ApoE(-)(/)(-) mice. (99m)Tc-TFI is promising for specific detection of inflammatory response in atherosclerotic plaques.
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA. Electronic address: zliu@radiology.arizona.edu.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Christy
authors.initials: C
authors.lastname: Barber
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.affiliation: AmProtein Cooperation, San Gabriel, CA, USA.
authors.forename: Mizhou M
authors.initials: MM
authors.lastname: Hui
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Lars R
authors.initials: LR
authors.lastname: Furenlid
authors.affiliation: Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Woolfenden
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D005260:Female; D007091:Image Processing, Computer-Assisted; D007249:Inflammation / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods*; D015609:Organotechnetium Compounds; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015609:Organotechnetium Compounds; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha
keywords: Apolipoprotein-E-deficient mice; Atherosclerosis; Inflammation; Interleukin-1; SPECT; Tumor necrosis factor