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Published on: September 26, 2018
Detection of atherosclerotic plaques in ApoE-deficient mice using (99m)Tc-duramycin
Zhonglin Liu1, Brandon T Larsen2, Lilach O Lerman3
1Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
Unlabelled:
Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, (99m)Tc-duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice.
Methods:
Atherosclerosis was induced in ApoE(-/-) mice by feeding an atherogenic diet. (99m)Tc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE(-/-) mice at 20weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE(-/-) mice (Group II) were imaged at 20 and 40weeks of age before sacrifice. Six ApoE wild-type (ApoE(+/+)) mice (Group III) were imaged at 40weeks as controls. Five additional ApoE(-/-) mice (40weeks of age) (Group IV) were imaged with a (99m)Tc-labeled inactive peptide, (99m)Tc-LinDUR, to assess (99m)Tc-duramycin targeting specificity.
Results:
Focal (99m)Tc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40weeks in the ApoE(-/-) mice but not in ApoE(+/+) mice. (99m)Tc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE(-/-) mice between 20 and 40weeks. Autoradiographic and histological data indicated significantly increased (99m)Tc-duramycin uptake in the ascending aorta and aortic arch associated with advanced plaques. Quantitative autoradiography showed that the ratio of activity in the aortic arch to descending thoracic aorta, which had no plaques or radioactive uptake, was 2.1 times higher at 40weeks than at 20weeks (6.62±0.89 vs. 3.18±0.29, P<0.01). There was barely detectable focal uptake of (99m)Tc-duramycin in the aortic arch of ApoE(+/+) mice. No detectable (99m)Tc-LinDUR uptake was observed in the aortas of ApoE(-/-) mice.
Conclusions:
PE-targeting properties of (99m)Tc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. (99m)Tc-duramycin is promising in localizing advanced atherosclerotic plaques.
Insights
This study shows that (99m)Tc-duramycin can detect atherosclerotic plaques in mice by targeting phosphatidylethanolamine (PE) exposure during apoptosis. The probe successfully localized plaque evolution and demonstrated specificity in apolipoprotein-E knockout mice.
Area of Science:
- Cardiovascular Research
- Molecular Imaging
- Biomedical Engineering
Background:
- Apoptosis of macrophages and smooth muscle cells contributes to atherosclerotic plaque destabilization.
- Exposure of phosphatidylethanolamine (PE) on the outer cell membrane during apoptosis serves as a biomarker.
- PE-specific probes offer a potential method for detecting and assessing atherosclerotic plaque evolution.
Purpose of the Study:
- To evaluate the efficacy of a PE-specific imaging probe, (99m)Tc-duramycin, for localizing atherosclerotic plaques.
- To assess plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice using (99m)Tc-duramycin.
- To determine the specificity of (99m)Tc-duramycin for atherosclerotic lesions.
Main Methods:
- Atherosclerosis was induced in ApoE(-/-) mice using an atherogenic diet.
- (99m)Tc-duramycin SPECT imaging was performed on ApoE(-/-) and control ApoE(+/+) mice at various ages.
- Ex vivo autoradiography and histology were used for validation.
- A non-targeting control probe, (99m)Tc-LinDUR, was used to assess specificity.
Main Results:
- Focal (99m)Tc-duramycin uptake was observed in the aortas of ApoE(-/-) mice, correlating with advanced plaques.
- Quantitative imaging showed a 2.2-fold increase in (99m)Tc-duramycin uptake in ApoE(-/-) mice between 20 and 40 weeks.
- Uptake was significantly higher in atherosclerotic lesions compared to non-lesional aorta and absent in control mice and with the non-targeting probe.
Conclusions:
- Noninvasive characterization of PE-targeting properties of (99m)Tc-duramycin in atherosclerotic mouse aortas was achieved.
- (99m)Tc-duramycin shows promise for localizing advanced atherosclerotic plaques.
- The probe's specificity and ability to track plaque evolution highlight its potential in cardiovascular research.
