Characterization of a novel model for atherosclerosis imaging: the apolipoprotein E-deficient rat

Jürgen W A Sijbesma; Aren van Waarde; Sebastiaan Kristensen; Ilse Kion; Uwe J F Tietge; Jan-Luuk Hillebrands; Marian L C Bulthuis; Hendrik Buikema; Dalibor Nakladal; Marit Westerterp; Fan Liu; Hendrikus H Boersma; Rudi A J O Dierckx; Riemer H J A Slart

doi:10.1186/s13550-023-01055-5

Characterization of a novel model for atherosclerosis imaging: the apolipoprotein E-deficient rat

EJNMMI Res. 2023 Dec 11;13(1):106. doi: 10.1186/s13550-023-01055-5.

Authors

Jürgen W A Sijbesma¹, Aren van Waarde², Sebastiaan Kristensen³, Ilse Kion², Uwe J F Tietge^{4

5}, Jan-Luuk Hillebrands⁶, Marian L C Bulthuis⁶, Hendrik Buikema⁷, Dalibor Nakladal^{7

8

9}, Marit Westerterp¹⁰, Fan Liu^{4

10}, Hendrikus H Boersma^{2

7}, Rudi A J O Dierckx², Riemer H J A Slart^{2

11}

Affiliations

¹ Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. j.w.a.sijbesma@umcg.nl.
² Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
³ Department of Electrical and Computer Engineering, Aarhus University, Aarhus, Denmark.
⁴ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵ Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.
⁶ Division of Pathology, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁷ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Comenius University Science Park, Bratislava, Slovakia.
⁹ 5th Department of Internal Medicine, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia.
¹⁰ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹¹ Faculty of Science and Technology, Department of Biomedical Photonic Imaging, University of Twente, Enschede, The Netherlands.

Abstract

Background: The apolipoprotein E-deficient (apoE^-/-) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE^-/- rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE^-/- rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging.

Results: ApoE^-/- rats showed significantly higher [¹⁸F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE^-/- rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and low-density lipoprotein fractions in the apoE^-/- rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE^-/- rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE^-/- rats.

Conclusion: These data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE^-/- rats. Therefore, this model shows promise for atherosclerosis imaging studies.

Keywords: Apolipoprotein E-deficient rat; Atherosclerosis; Positron emission tomography (PET); [18F]2-fluoro-2-deoxy-D-glucose.

Abstract

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