Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a (99m)Tc-labeled dual-domain cytokine ligand

Nucl Med Biol. 2014 Nov-Dec;41(10):785-92. doi: 10.1016/j.nucmedbio.2014.08.004. Epub 2014 Aug 7.

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.

Keywords: Apolipoprotein-E-deficient mice; Atherosclerosis; Inflammation; Interleukin-1; SPECT; Tumor necrosis factor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoproteins E / physiology*
  • Atherosclerosis / complications
  • Atherosclerosis / diagnosis*
  • Atherosclerosis / metabolism
  • Female
  • Image Processing, Computer-Assisted
  • Inflammation / complications
  • Inflammation / diagnosis*
  • Inflammation / metabolism
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Imaging / methods*
  • Organotechnetium Compounds*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Tomography, Emission-Computed, Single-Photon / methods
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Apolipoproteins E
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Organotechnetium Compounds
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha