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Updated: Jun 2, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
ADAMTS4-Specific MR Peptide Probe for the Assessment of Atherosclerotic Plaque Burden in a Mouse Model
Dilyana B Mangarova1, Jan O Kaufmann, Julia Brangsch
1From the Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany (D.B.M., J.O.K., J.B., A.K., J.M., J.L.H., C.R., M.T., B.H., M.R.M.); Department of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany (D.B.M., J.O.K., J.B., A.K., L.C.A., M.R.M.); Department of Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany (J.O.K.); Division 1.5 Protein Analysis, Federal Institute for Materials Research and Testing, Berlin, Germany (J.O.K., M.G.W.); Department of Biology, Chemistry, and Pharmacy, Institute of Biology, Freie Universität Berlin, Berlin, Germany (A.K.); Department of Veterinary Medicine, Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Freie Universität Berlin, Berlin, Germany (J.L.H.); Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany (C.V., P.N., U.K.); Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany (A.L.); DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany (A.L.); and Division of Cardiology, Massachusetts General Hospital, Harvard University, Boston, MA (W.C.P.).
Introduction:
Atherosclerosis is the underlying cause of multiple cardiovascular pathologies. The present-day clinical imaging modalities do not offer sufficient information on plaque composition or rupture risk. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a strongly upregulated proteoglycan-cleaving enzyme that is specific to cardiovascular diseases, inter alia, atherosclerosis.
Materials And Methods:
Male apolipoprotein E-deficient mice received a high-fat diet for 2 (n = 11) or 4 months (n = 11). Additionally, a group (n = 11) receiving pravastatin by drinking water for 4 months alongside the high-fat diet was examined. The control group (n = 10) consisted of C57BL/6J mice on standard chow. Molecular magnetic resonance imaging was performed prior to and after administration of the gadolinium (Gd)-based ADAMTS4-specific probe, followed by ex vivo analyses of the aortic arch, brachiocephalic arteries, and carotid arteries. A P value <0.05 was considered to indicate a statistically significant difference.
Results:
With advancing atherosclerosis, a significant increase in the contrast-to-noise ratio was measured after intravenous application of the probe (mean precontrast = 2.25; mean postcontrast = 11.47, P < 0.001 in the 4-month group). The pravastatin group presented decreased ADAMTS4 expression. A strong correlation between ADAMTS4 content measured via immunofluorescence staining and an increase in the contrast-to-noise ratio was detected ( R2 = 0.69). Microdissection analysis revealed that ADAMTS4 gene expression in the plaque area was significantly greater than that in the arterial wall of a control mouse ( P < 0.001). Laser ablation-inductively coupled plasma-mass spectrometry confirmed strong colocalization of areas positive for ADAMTS4 and Gd.
Conclusions:
Magnetic resonance imaging using an ADAMTS4-specific agent is a promising method for characterizing atherosclerotic plaques and could improve plaque assessment in the diagnosis and treatment of atherosclerosis.
