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Noninvasive Imaging of Atherosclerotic Lesions in Apolipoprotein E–Deficient and Low-Density-Lipoprotein Receptor–Deficient Mice with Annexin A5

¹ Division of Cardiology, University of California, Irvine School of Medicine, Irvine, California; ² Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, California; ³ Department of Cardiology, Maastricht University Hospital, Maastricht, The Netherlands; ⁴ Division of Biochemistry, Maastricht University, Maastricht, The Netherlands; ⁵ Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; ⁶ Armed Forces Institute of Pathology, Washington, District of Columbia; and ⁷ Department of Pathology, University of California, Irvine School of Medicine, Irvine, California

Correspondence: For correspondence or reprints contact: Artiom Petrov, PhD, Division of Cardiology, University of California, Irvine School of Medicine, Medical Science Building I, Room C 112, Irvine, CA 92697. E-mail: adpetrov{at}uci.edu

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.

Key Words: apoE^–/– mice • LDLR^–/– mice • cholesterol diet • apoptosis • ^99mTc-annexin A5

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