Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5

Satoshi Isobe, Sotirios Tsimikas, Jun Zhou, Shinichiro Fujimoto, Masayoshi Sarai, Michael J. Branks, Ai Fujimoto, Leonard Hofstra, Chris P. Reutelingsperger, Toyoaki Murohara, Renu Virmani, Frank D. Kolodgie, Navneet Narula, Artiom Petrov, Jagat Narula

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Abstract

Transgenic mice such as apolipoprotein E-deficient (apoE-/-) and low-density-lipoprotein receptor-deficient (LDLR-/-) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. Radiolabeled annexin A5 has been successfully used to noninvasively image experimental and clinical atherosclerotic disease. We evaluated the feasibility of annexin A5 imaging in transgenic apoE-/- and LDLR-/- mice with or without a cholesterol diet. Methods: Thirty-three mice (mean age, 62 ± 0.9 wk old) were used. Of these 33 mice, apoE-/- mice with the cholesterol diet for 4 mo (n = 5) and without the cholesterol diet (n = 8) and LDLR-/- mice with the cholesterol diet for 6 mo (n = 7) and without the cholesterol diet (n = 7) were compared with 6 normal wild-type (C57BL/6) mice with the same genetic background. 99mTc-annexin A5 was injected in 31 animals for noninvasive imaging using micro-SPECT/CT. After in vivo micro-SPECT/CT, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram (%ID/g) annexin uptake, followed by histologic and immunohistochemical characterization. For the evaluation of precise target localization, biotinylated annexin A5 was injected in the remaining 2 normally fed apoE-/- mice. Results: Aortic lesions were clearly visualized noninvasively by micro-SPECT and aorta calcification was detectable by micro-CT. The quantitative uptake of annexin A5 was highest in the cholesterol-fed apoE-/- (0.88 ± 0.27 %ID/g) mice, followed by the normal chow-fed apoE-/- (0.60 ± 0.16%ID/g), the cholesterol-fed LDLR-/- (0.59 ± 0.14 %ID/g), the chow-fed LDLR-/- (0.40 ± 0.31 %ID/g), and the control (0.15 ± 0.05 %ID/g) mice. The histologic extent of atherosclerosis paralleled radiotracer uptake, and immunohistochemical studies revealed a significant correlation between radiotracer uptake and both macrophage infiltration and the extent of apoptosis. Intravenously injected biotinylated annexin A5 localized in apoptotic and nonapoptotic macrophages. Conclusion: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled annexin A5 in transgenic mouse models of human atherosclerosis.

Original languageEnglish
Pages (from-to)1497-1505
Number of pages9
JournalJournal of Nuclear Medicine
Volume47
Issue number9
Publication statusPublished - 01-09-2006

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LDL Receptors
Annexin A5
Apolipoproteins E
Cholesterol
Diet
Atherosclerosis
Transgenic Mice
Aorta
Macrophages
Annexins
Feasibility Studies
Hypercholesterolemia
Single-Photon Emission-Computed Tomography
Inbred C57BL Mouse
Apoptosis

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Isobe, Satoshi ; Tsimikas, Sotirios ; Zhou, Jun ; Fujimoto, Shinichiro ; Sarai, Masayoshi ; Branks, Michael J. ; Fujimoto, Ai ; Hofstra, Leonard ; Reutelingsperger, Chris P. ; Murohara, Toyoaki ; Virmani, Renu ; Kolodgie, Frank D. ; Narula, Navneet ; Petrov, Artiom ; Narula, Jagat. / Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5. In: Journal of Nuclear Medicine. 2006 ; Vol. 47, No. 9. pp. 1497-1505.
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abstract = "Transgenic mice such as apolipoprotein E-deficient (apoE-/-) and low-density-lipoprotein receptor-deficient (LDLR-/-) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. Radiolabeled annexin A5 has been successfully used to noninvasively image experimental and clinical atherosclerotic disease. We evaluated the feasibility of annexin A5 imaging in transgenic apoE-/- and LDLR-/- mice with or without a cholesterol diet. Methods: Thirty-three mice (mean age, 62 ± 0.9 wk old) were used. Of these 33 mice, apoE-/- mice with the cholesterol diet for 4 mo (n = 5) and without the cholesterol diet (n = 8) and LDLR-/- mice with the cholesterol diet for 6 mo (n = 7) and without the cholesterol diet (n = 7) were compared with 6 normal wild-type (C57BL/6) mice with the same genetic background. 99mTc-annexin A5 was injected in 31 animals for noninvasive imaging using micro-SPECT/CT. After in vivo micro-SPECT/CT, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram ({\%}ID/g) annexin uptake, followed by histologic and immunohistochemical characterization. For the evaluation of precise target localization, biotinylated annexin A5 was injected in the remaining 2 normally fed apoE-/- mice. Results: Aortic lesions were clearly visualized noninvasively by micro-SPECT and aorta calcification was detectable by micro-CT. The quantitative uptake of annexin A5 was highest in the cholesterol-fed apoE-/- (0.88 ± 0.27 {\%}ID/g) mice, followed by the normal chow-fed apoE-/- (0.60 ± 0.16{\%}ID/g), the cholesterol-fed LDLR-/- (0.59 ± 0.14 {\%}ID/g), the chow-fed LDLR-/- (0.40 ± 0.31 {\%}ID/g), and the control (0.15 ± 0.05 {\%}ID/g) mice. The histologic extent of atherosclerosis paralleled radiotracer uptake, and immunohistochemical studies revealed a significant correlation between radiotracer uptake and both macrophage infiltration and the extent of apoptosis. Intravenously injected biotinylated annexin A5 localized in apoptotic and nonapoptotic macrophages. Conclusion: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled annexin A5 in transgenic mouse models of human atherosclerosis.",
author = "Satoshi Isobe and Sotirios Tsimikas and Jun Zhou and Shinichiro Fujimoto and Masayoshi Sarai and Branks, {Michael J.} and Ai Fujimoto and Leonard Hofstra and Reutelingsperger, {Chris P.} and Toyoaki Murohara and Renu Virmani and Kolodgie, {Frank D.} and Navneet Narula and Artiom Petrov and Jagat Narula",
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Isobe, S, Tsimikas, S, Zhou, J, Fujimoto, S, Sarai, M, Branks, MJ, Fujimoto, A, Hofstra, L, Reutelingsperger, CP, Murohara, T, Virmani, R, Kolodgie, FD, Narula, N, Petrov, A & Narula, J 2006, 'Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5', Journal of Nuclear Medicine, vol. 47, no. 9, pp. 1497-1505.

Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5. / Isobe, Satoshi; Tsimikas, Sotirios; Zhou, Jun; Fujimoto, Shinichiro; Sarai, Masayoshi; Branks, Michael J.; Fujimoto, Ai; Hofstra, Leonard; Reutelingsperger, Chris P.; Murohara, Toyoaki; Virmani, Renu; Kolodgie, Frank D.; Narula, Navneet; Petrov, Artiom; Narula, Jagat.

In: Journal of Nuclear Medicine, Vol. 47, No. 9, 01.09.2006, p. 1497-1505.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5

AU - Isobe, Satoshi

AU - Tsimikas, Sotirios

AU - Zhou, Jun

AU - Fujimoto, Shinichiro

AU - Sarai, Masayoshi

AU - Branks, Michael J.

AU - Fujimoto, Ai

AU - Hofstra, Leonard

AU - Reutelingsperger, Chris P.

AU - Murohara, Toyoaki

AU - Virmani, Renu

AU - Kolodgie, Frank D.

AU - Narula, Navneet

AU - Petrov, Artiom

AU - Narula, Jagat

PY - 2006/9/1

Y1 - 2006/9/1

N2 - Transgenic mice such as apolipoprotein E-deficient (apoE-/-) and low-density-lipoprotein receptor-deficient (LDLR-/-) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. Radiolabeled annexin A5 has been successfully used to noninvasively image experimental and clinical atherosclerotic disease. We evaluated the feasibility of annexin A5 imaging in transgenic apoE-/- and LDLR-/- mice with or without a cholesterol diet. Methods: Thirty-three mice (mean age, 62 ± 0.9 wk old) were used. Of these 33 mice, apoE-/- mice with the cholesterol diet for 4 mo (n = 5) and without the cholesterol diet (n = 8) and LDLR-/- mice with the cholesterol diet for 6 mo (n = 7) and without the cholesterol diet (n = 7) were compared with 6 normal wild-type (C57BL/6) mice with the same genetic background. 99mTc-annexin A5 was injected in 31 animals for noninvasive imaging using micro-SPECT/CT. After in vivo micro-SPECT/CT, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram (%ID/g) annexin uptake, followed by histologic and immunohistochemical characterization. For the evaluation of precise target localization, biotinylated annexin A5 was injected in the remaining 2 normally fed apoE-/- mice. Results: Aortic lesions were clearly visualized noninvasively by micro-SPECT and aorta calcification was detectable by micro-CT. The quantitative uptake of annexin A5 was highest in the cholesterol-fed apoE-/- (0.88 ± 0.27 %ID/g) mice, followed by the normal chow-fed apoE-/- (0.60 ± 0.16%ID/g), the cholesterol-fed LDLR-/- (0.59 ± 0.14 %ID/g), the chow-fed LDLR-/- (0.40 ± 0.31 %ID/g), and the control (0.15 ± 0.05 %ID/g) mice. The histologic extent of atherosclerosis paralleled radiotracer uptake, and immunohistochemical studies revealed a significant correlation between radiotracer uptake and both macrophage infiltration and the extent of apoptosis. Intravenously injected biotinylated annexin A5 localized in apoptotic and nonapoptotic macrophages. Conclusion: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled annexin A5 in transgenic mouse models of human atherosclerosis.

AB - Transgenic mice such as apolipoprotein E-deficient (apoE-/-) and low-density-lipoprotein receptor-deficient (LDLR-/-) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. Radiolabeled annexin A5 has been successfully used to noninvasively image experimental and clinical atherosclerotic disease. We evaluated the feasibility of annexin A5 imaging in transgenic apoE-/- and LDLR-/- mice with or without a cholesterol diet. Methods: Thirty-three mice (mean age, 62 ± 0.9 wk old) were used. Of these 33 mice, apoE-/- mice with the cholesterol diet for 4 mo (n = 5) and without the cholesterol diet (n = 8) and LDLR-/- mice with the cholesterol diet for 6 mo (n = 7) and without the cholesterol diet (n = 7) were compared with 6 normal wild-type (C57BL/6) mice with the same genetic background. 99mTc-annexin A5 was injected in 31 animals for noninvasive imaging using micro-SPECT/CT. After in vivo micro-SPECT/CT, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram (%ID/g) annexin uptake, followed by histologic and immunohistochemical characterization. For the evaluation of precise target localization, biotinylated annexin A5 was injected in the remaining 2 normally fed apoE-/- mice. Results: Aortic lesions were clearly visualized noninvasively by micro-SPECT and aorta calcification was detectable by micro-CT. The quantitative uptake of annexin A5 was highest in the cholesterol-fed apoE-/- (0.88 ± 0.27 %ID/g) mice, followed by the normal chow-fed apoE-/- (0.60 ± 0.16%ID/g), the cholesterol-fed LDLR-/- (0.59 ± 0.14 %ID/g), the chow-fed LDLR-/- (0.40 ± 0.31 %ID/g), and the control (0.15 ± 0.05 %ID/g) mice. The histologic extent of atherosclerosis paralleled radiotracer uptake, and immunohistochemical studies revealed a significant correlation between radiotracer uptake and both macrophage infiltration and the extent of apoptosis. Intravenously injected biotinylated annexin A5 localized in apoptotic and nonapoptotic macrophages. Conclusion: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled annexin A5 in transgenic mouse models of human atherosclerosis.

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