Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis.

Yared Tekabe, Qing Li, Rosa Rosario, Marija Sedlar, Stan Majewski, Barry Hudson, Andrew J. Einstein, Ann Marie Schmidt, Lynne L. Johnson

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: The receptor for advanced glycation end products (RAGE) is implicated in the development and progression of atherosclerosis. We tested the hypothesis that (99m)Tc-labeled anti-RAGE F(ab')(2) can be used as a noninvasive tool to image atherosclerotic lesions in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: A sequence in the V-type Ig extracellular domain of RAGE was used to develop a peptide injected into rabbits; serum was retrieved, IgG prepared and affinity-purified, and pepsin-digested into F(ab')(2). Thirteen 6-week apoE(-/-) mice were fed a Western diet. At 20 weeks, 6 were injected with 15.2+/-1.9 MBq (350 to 411 microCi) (99m)Tc-labeled anti-RAGE F(ab')(2), 6 were injected with (99m)Tc-labeled control nonspecific IgG F(ab')(2), and 1 was injected with dual-labeled (99m)Tc and rhodamine anti-RAGE F(ab')(2). Four 20-week C57BL/6 mice were injected with (99m)Tc-labeled anti-RAGE F(ab')(2). All mice were imaged on a high resolution mini-gamma camera 4 hours after injection and euthanized. The aortic tree was dissected and photographed, and the proximal aorta was sectioned for staining after gamma scintillation counting. All 6 apoE(-/-) mice injected with (99m)Tc-labeled anti-RAGE F(ab')(2) fragments showed focal tracer uptake in the proximal aorta (mean %ID/g, 1.98%). Disease and antibody controls showed no focal tracer uptake in the thorax (%ID/g, <1.0%). Histological sections of the proximal aorta showed American Heart Association class III lesions with lipid laden macrophages, smooth muscle cells, and positive staining for RAGE. On immunofluorescence, RAGE colocalized with macrophages. CONCLUSIONS: These data show the feasibility of noninvasively imaging RAGE in atherosclerotic lesions in a murine model and confirm levels of RAGE expression sufficient to allow detection on in vivo imaging.

Original languageEnglish
Pages (from-to)212-219
Number of pages8
JournalCirculation. Cardiovascular imaging
Volume1
Issue number3
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

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Atherosclerotic Plaques
Atherosclerosis
Apolipoproteins E
Aorta
Advanced Glycosylation End Product-Specific Receptor
Immunoglobulin G
Macrophages
Staining and Labeling
Scintillation Counting
Gamma Cameras
Rhodamines
Pepsin A
Inbred C57BL Mouse
Smooth Muscle Myocytes
Fluorescent Antibody Technique
Thorax
Rabbits
Lipids
Peptides
Injections

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis. / Tekabe, Yared; Li, Qing; Rosario, Rosa; Sedlar, Marija; Majewski, Stan; Hudson, Barry; Einstein, Andrew J.; Schmidt, Ann Marie; Johnson, Lynne L.

In: Circulation. Cardiovascular imaging, Vol. 1, No. 3, 01.11.2008, p. 212-219.

Research output: Contribution to journalArticle

Tekabe, Yared ; Li, Qing ; Rosario, Rosa ; Sedlar, Marija ; Majewski, Stan ; Hudson, Barry ; Einstein, Andrew J. ; Schmidt, Ann Marie ; Johnson, Lynne L. / Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis. In: Circulation. Cardiovascular imaging. 2008 ; Vol. 1, No. 3. pp. 212-219.
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AU - Li, Qing

AU - Rosario, Rosa

AU - Sedlar, Marija

AU - Majewski, Stan

AU - Hudson, Barry

AU - Einstein, Andrew J.

AU - Schmidt, Ann Marie

AU - Johnson, Lynne L.

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N2 - BACKGROUND: The receptor for advanced glycation end products (RAGE) is implicated in the development and progression of atherosclerosis. We tested the hypothesis that (99m)Tc-labeled anti-RAGE F(ab')(2) can be used as a noninvasive tool to image atherosclerotic lesions in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: A sequence in the V-type Ig extracellular domain of RAGE was used to develop a peptide injected into rabbits; serum was retrieved, IgG prepared and affinity-purified, and pepsin-digested into F(ab')(2). Thirteen 6-week apoE(-/-) mice were fed a Western diet. At 20 weeks, 6 were injected with 15.2+/-1.9 MBq (350 to 411 microCi) (99m)Tc-labeled anti-RAGE F(ab')(2), 6 were injected with (99m)Tc-labeled control nonspecific IgG F(ab')(2), and 1 was injected with dual-labeled (99m)Tc and rhodamine anti-RAGE F(ab')(2). Four 20-week C57BL/6 mice were injected with (99m)Tc-labeled anti-RAGE F(ab')(2). All mice were imaged on a high resolution mini-gamma camera 4 hours after injection and euthanized. The aortic tree was dissected and photographed, and the proximal aorta was sectioned for staining after gamma scintillation counting. All 6 apoE(-/-) mice injected with (99m)Tc-labeled anti-RAGE F(ab')(2) fragments showed focal tracer uptake in the proximal aorta (mean %ID/g, 1.98%). Disease and antibody controls showed no focal tracer uptake in the thorax (%ID/g, <1.0%). Histological sections of the proximal aorta showed American Heart Association class III lesions with lipid laden macrophages, smooth muscle cells, and positive staining for RAGE. On immunofluorescence, RAGE colocalized with macrophages. CONCLUSIONS: These data show the feasibility of noninvasively imaging RAGE in atherosclerotic lesions in a murine model and confirm levels of RAGE expression sufficient to allow detection on in vivo imaging.

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