Investigative radiology · 2025
ADAMTS4-Specific MR Peptide Probe for the Assessment of Atherosclerotic Plaque Burden in a Mouse Model.
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Mangarova Dilyana B, Kaufmann Jan O, Brangsch Julia, Kader Avan, Möckel Jana, Heyl Jennifer L, Verlemann Christine, Adams Lisa C, Ludwig Antje, Reimann Carolin, Poller Wolfram C, Niehaus Peter, Karst Uwe, Taupitz Matthias, Hamm Bernd, Weller Michael G, Makowski Marcus R
Аннотация
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.
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.