Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin

Zhonglin Liu, Brandon Larsen, Lilach O Lerman, Brian D. Gray, Christy Barber, Ahmad F. Hedayat, Ming Zhao, Lars R. Furenlid, Koon Y. Pak, James M. Woolfenden

Research output: Contribution to journalArticle

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Abstract

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, 99mTc-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. 99mTc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE−/− mice at 20 weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE−/− mice (Group II) were imaged at 20 and 40 weeks of age before sacrifice. Six ApoE wild-type (ApoE+/+) mice (Group III) were imaged at 40 weeks as controls. Five additional ApoE−/− mice (40 weeks of age) (Group IV) were imaged with a 99mTc-labeled inactive peptide, 99mTc-LinDUR, to assess 99mTc-duramycin targeting specificity. Results Focal 99mTc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40 weeks in the ApoE−/− mice but not in ApoE+/+ mice. 99mTc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE−/− mice between 20 and 40 weeks. Autoradiographic and histological data indicated significantly increased 99mTc-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 40 weeks than at 20 weeks (6.62 ± 0.89 vs. 3.18 ± 0.29, P < 0.01). There was barely detectable focal uptake of 99mTc-duramycin in the aortic arch of ApoE+/+ mice. No detectable 99mTc-LinDUR uptake was observed in the aortas of ApoE−/− mice. Conclusions PE-targeting properties of 99mTc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. 99mTc-duramycin is promising in localizing advanced atherosclerotic plaques.

Original languageEnglish (US)
Pages (from-to)496-505
Number of pages10
JournalNuclear Medicine and Biology
Volume43
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Apolipoproteins E
Atherosclerotic Plaques
Knockout Mice
Thoracic Aorta
Aorta
technetium 99m HYNIC-duramycin
Age Groups
Atherogenic Diet
Apoptosis
Single-Photon Emission-Computed Tomography
Autoradiography
Smooth Muscle Myocytes
Atherosclerosis
Macrophages
Cell Membrane

Keywords

  • Atherosclerosis
  • Duramycin
  • Phosphatidylethanolamine
  • SPECT

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin. / Liu, Zhonglin; Larsen, Brandon; Lerman, Lilach O; Gray, Brian D.; Barber, Christy; Hedayat, Ahmad F.; Zhao, Ming; Furenlid, Lars R.; Pak, Koon Y.; Woolfenden, James M.

In: Nuclear Medicine and Biology, Vol. 43, No. 8, 01.08.2016, p. 496-505.

Research output: Contribution to journalArticle

Liu, Z, Larsen, B, Lerman, LO, Gray, BD, Barber, C, Hedayat, AF, Zhao, M, Furenlid, LR, Pak, KY & Woolfenden, JM 2016, 'Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin', Nuclear Medicine and Biology, vol. 43, no. 8, pp. 496-505. https://doi.org/10.1016/j.nucmedbio.2016.05.007
Liu, Zhonglin ; Larsen, Brandon ; Lerman, Lilach O ; Gray, Brian D. ; Barber, Christy ; Hedayat, Ahmad F. ; Zhao, Ming ; Furenlid, Lars R. ; Pak, Koon Y. ; Woolfenden, James M. / Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin. In: Nuclear Medicine and Biology. 2016 ; Vol. 43, No. 8. pp. 496-505.
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abstract = "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, 99mTc-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. 99mTc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE−/− mice at 20 weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE−/− mice (Group II) were imaged at 20 and 40 weeks of age before sacrifice. Six ApoE wild-type (ApoE+/+) mice (Group III) were imaged at 40 weeks as controls. Five additional ApoE−/− mice (40 weeks of age) (Group IV) were imaged with a 99mTc-labeled inactive peptide, 99mTc-LinDUR, to assess 99mTc-duramycin targeting specificity. Results Focal 99mTc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40 weeks in the ApoE−/− mice but not in ApoE+/+ mice. 99mTc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE−/− mice between 20 and 40 weeks. Autoradiographic and histological data indicated significantly increased 99mTc-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 40 weeks than at 20 weeks (6.62 ± 0.89 vs. 3.18 ± 0.29, P < 0.01). There was barely detectable focal uptake of 99mTc-duramycin in the aortic arch of ApoE+/+ mice. No detectable 99mTc-LinDUR uptake was observed in the aortas of ApoE−/− mice. Conclusions PE-targeting properties of 99mTc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. 99mTc-duramycin is promising in localizing advanced atherosclerotic plaques.",
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author = "Zhonglin Liu and Brandon Larsen and Lerman, {Lilach O} and Gray, {Brian D.} and Christy Barber and Hedayat, {Ahmad F.} and Ming Zhao and Furenlid, {Lars R.} and Pak, {Koon Y.} and Woolfenden, {James M.}",
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AU - Larsen, Brandon

AU - Lerman, Lilach O

AU - Gray, Brian D.

AU - Barber, Christy

AU - Hedayat, Ahmad F.

AU - Zhao, Ming

AU - Furenlid, Lars R.

AU - Pak, Koon Y.

AU - Woolfenden, James M.

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N2 - 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, 99mTc-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. 99mTc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE−/− mice at 20 weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE−/− mice (Group II) were imaged at 20 and 40 weeks of age before sacrifice. Six ApoE wild-type (ApoE+/+) mice (Group III) were imaged at 40 weeks as controls. Five additional ApoE−/− mice (40 weeks of age) (Group IV) were imaged with a 99mTc-labeled inactive peptide, 99mTc-LinDUR, to assess 99mTc-duramycin targeting specificity. Results Focal 99mTc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40 weeks in the ApoE−/− mice but not in ApoE+/+ mice. 99mTc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE−/− mice between 20 and 40 weeks. Autoradiographic and histological data indicated significantly increased 99mTc-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 40 weeks than at 20 weeks (6.62 ± 0.89 vs. 3.18 ± 0.29, P < 0.01). There was barely detectable focal uptake of 99mTc-duramycin in the aortic arch of ApoE+/+ mice. No detectable 99mTc-LinDUR uptake was observed in the aortas of ApoE−/− mice. Conclusions PE-targeting properties of 99mTc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. 99mTc-duramycin is promising in localizing advanced atherosclerotic plaques.

AB - 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, 99mTc-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. 99mTc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE−/− mice at 20 weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE−/− mice (Group II) were imaged at 20 and 40 weeks of age before sacrifice. Six ApoE wild-type (ApoE+/+) mice (Group III) were imaged at 40 weeks as controls. Five additional ApoE−/− mice (40 weeks of age) (Group IV) were imaged with a 99mTc-labeled inactive peptide, 99mTc-LinDUR, to assess 99mTc-duramycin targeting specificity. Results Focal 99mTc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40 weeks in the ApoE−/− mice but not in ApoE+/+ mice. 99mTc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE−/− mice between 20 and 40 weeks. Autoradiographic and histological data indicated significantly increased 99mTc-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 40 weeks than at 20 weeks (6.62 ± 0.89 vs. 3.18 ± 0.29, P < 0.01). There was barely detectable focal uptake of 99mTc-duramycin in the aortic arch of ApoE+/+ mice. No detectable 99mTc-LinDUR uptake was observed in the aortas of ApoE−/− mice. Conclusions PE-targeting properties of 99mTc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. 99mTc-duramycin is promising in localizing advanced atherosclerotic plaques.

KW - Atherosclerosis

KW - Duramycin

KW - Phosphatidylethanolamine

KW - SPECT

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