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Nuclear Medicine and Molecular Imaging

, Volume 52, Issue 2, pp 144–153 | Cite as

123I–Labeled oxLDL Is Widely Distributed Throughout the Whole Body in Mice

  • Atushi Nakano
  • Hidekazu Kawashima
  • Yoshinori Miyake
  • Tsutomu Zeniya
  • Akihide Yamamoto
  • Kazuhiro Koshino
  • Takashi Temma
  • Tetsuya Fukuda
  • Yoshiko Fujita
  • Akemi Kakino
  • Shigehiko Kanaya
  • Tatsuya Sawamura
  • Hidehiro Iida
Original Article

Abstract

Purpose

Oxidized low-density lipoprotein (oxLDL) plays a key role in endothelial dysfunction, vascular inflammation, and atherogenesis. The aim of this study was to assess blood clearance and in vivo kinetics of radiolabeled oxLDL in mice.

Methods

We synthesized 123I–oxLDL by the iodine monochloride method, and performed an uptake study in CHO cells transfected with lectin-like oxLDL receptor-1 (LOX-1). In addition, we evaluated the consistency between the 123I–oxLDL autoradiogram and the fluorescence image of DiI-oxLDL after intravenous injection for both spleen and liver. Whole-body dynamic planar images were acquired 10 min post injection of 123I–oxLDL to generate regional time-activity curves (TACs) of the liver, heart, lungs, kidney, head, and abdomen. Regional radioactivity for those excised tissues as well as the bladder, stomach, gut, and thyroid were assessed using a gamma counter, yielding percent injected dose (%ID) and dose uptake ratio (DUR). The presence of 123I–oxLDL in serum was assessed by radio-HPLC.

Results

The cellular uptakes of 123I–oxLDL were identical to those of DiI-oxLDL, and autoradiograms and fluorescence images also exhibited consistent distributions. TACs after injection of 123I–oxLDL demonstrated extremely fast kinetics. The radioactivity uptake at 10 min post-injection was highest in the liver (40.8 ± 2.4% ID). Notably, radioactivity uptake was equivalent throughout the rest of the body (39.4 ± 2.7% ID). HPLC analysis revealed no remaining 123I–oxLDL or its metabolites in the blood.

Conclusion

123I–OxLDL was widely distributed not only in the liver, but also throughout the whole body, providing insight into the pathophysiological effects of oxLDL.

Keywords

Oxidized low-density lipoprotein (oxLDL) Radiolabeled ligand Dynamic planar imaging Biodistribution 

Notes

Acknowledgements

The authors would like to thank Dr. Kyoko Shioya, DVM from Laboratory of Animal Experiment and Medicine Management, National Cerebral and Cardiovascular Center, Osaka, Japan, for her assistance and advise on animal care and experimental procedures.

Compliance with Ethical Standards

Conflict of Interest

Atushi Nakano, Hidekazu Kawashima, Yoshinori Miyake, Tsutomu Zeniya, Kazuhiro Koshino, Takashi Temma, Tetsuya Fukuda, Yoshiko Fujita, Akemi Kakino, Shigehiko Kanaya, and Tatsuya Sawamura declare that they have no conflict of interest. Hidehiro Iida received research grants from Chugai Yakuhin, Japan, Nihon Medi Physics, Japan and Molecular Imaging Labo, Japan. Akihide Yamamoto is paid by Molecular Imaging lab, Japan. This study was supported by the Budget for Nuclear Research of MEXT (Ministry of Education, Culture, Sports, Science and Technology Japan), a Grant for Translational Research from MHLW (Ministry of Health, Labor and Welfare, Japan), a Grant for Strategic Japanese-Finnish Research Cooperative Program on “Application of Medical ICT Devices” from Japan Agency for Medical Research and Development (AMED), Japan, and JSPS KAKENHI Grants (Number: 24,601,021 and 15 K01309).

Ethical Approval

The animal experiments in this study were conducted in accordance with guidelines for animal research on Human Care and Use of Laboratory Animals (Rockville, National Institute of Health/Office for Protection from Research Risks, 1996). The study protocol was approved by the Sub-committee for Laboratory Animal Welfare, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.

Informed Consent

The present study included only animal data, thus our institute approved that the requirement to obtain informed consent was waived.

References

  1. 1.
    Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340(2):115–26.CrossRefPubMedGoogle Scholar
  2. 2.
    Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001;104(4):503–16.CrossRefPubMedGoogle Scholar
  4. 4.
    Kopprasch S, Pietzsch J, Ansurudeen I, et al. Prediabetic and diabetic in vivo modification of circulating low-density lipoprotein attenuates its stimulatory effect on adrenal aldosterone and cortisol secretion. J Endocrinol. 2009;200(1):45–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Portelinha A, Belo L, Cerdeira AS, et al. Lipid levels including oxidized LDL in women with history of preeclampsia. Hypertens Pregnancy. 2010;29(1):93–100.CrossRefPubMedGoogle Scholar
  6. 6.
    Dai L, Zhang Z, Winyard PG, et al. A modified form of low-density lipoprotein with increased electronegative charge is present in rheumatoid arthritis synovial fluid. Free Radic Biol Med. 1997;22(4):705–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Meisinger C, Baumert J, Khuseyinova N, Loewel H, Koenig W. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation. 2005;112(5):651–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Inoue N, Okamura T, Kokubo Y, et al. LOX index, a novel predictive biochemical marker for coronary heart disease and stroke. Clin Chem. 2010;56(4):550–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR Jr. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA. 2008;299(19):2287–93.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Van Berkel TJ, De Rijke YB, Kruijt JK. Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells. J Biol Chem. 1991;266(4):2282–9.PubMedGoogle Scholar
  11. 11.
    Kamps JA, Kruijt JK, Kuiper J, van Berkel TJ. Characterization of the interaction of acetylated LDL and oxidatively modified LDL with human liver parenchymal and Kupffer cells in culture. Arterioscler Thromb. 1992;12(9):1079–87.CrossRefPubMedGoogle Scholar
  12. 12.
    Ueda Y, Arai H, Kawashima A, et al. Different expression of modified low density lipoprotein receptors in rabbit peritoneal macrophages and Kupffer cells. Atherosclerosis. 1993;101(1):25–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Ling W, Lougheed M, Suzuki H, Buchan A, Kodama T, Steinbrecher UP. Oxidized or acetylated low density lipoproteins are rapidly cleared by the liver in mice with disruption of the scavenger receptor class a type I/II gene. J Clin Invest. 1997;100(2):244–52.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Steinbrecher UP, Witztum JL, Parthasarathy S, Steinberg D. Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. Arteriosclerosis. 1987;7(2):135–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Iuliano L, Signore A, Vallabajosula S, et al. Preparation and biodistribution of 99m technetium labelled oxidized LDL in man. Atherosclerosis. 1996;126(1):131–41.CrossRefPubMedGoogle Scholar
  16. 16.
    Iida H, Nakagawara J, Hayashida K, et al. Multicenter evaluation of a standardized protocol for rest and acetazolamide cerebral blood flow assessment using a quantitative SPECT reconstruction program and split-dose 123I-iodoamphetamine. J Nucl Med. 2010;51(10):1624–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Iida H, Narita Y, Kado H, et al. Effects of scatter and attenuation correction on quantitative assessment of regional cerebral blood flow with SPECT. J Nucl Med. 1998;39(1):181–9.PubMedGoogle Scholar
  18. 18.
    Fujita Y, Kakino A, Nishimichi N, et al. Oxidized LDL receptor LOX-1 binds to C-reactive protein and mediates its vascular effects. Clin Chem. 2009;55(2):285–94.CrossRefPubMedGoogle Scholar
  19. 19.
    Sawamura T, Kume N, Aoyama T, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Atsma DE, Kempen HJ, Nieuwenhuizen W, van’t Hooft FM. Pauwels EK. Partial characterization of low density lipoprotein preparations isolated from fresh and frozen plasma after radiolabeling by seven different methods. J Lipid Res. 1991;32(1):173–81.PubMedGoogle Scholar
  21. 21.
    Gullapalli RR, Demirel MC, Butler PJ. Molecular dynamics simulations of DiI-C18(3) in a DPPC lipid bilayer. Phys Chem Chem Phys. 2008;10(24):3548–60.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yamamoto A, Sato H, Enmi J, et al. Use of a clinical MRI scanner for preclinical research on rats. Radiol Phys Technol. 2009;2(1):13–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82.CrossRefPubMedGoogle Scholar
  24. 24.
    Loening AM, Gambhir SS. AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging. 2003;2(3):131–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Diehl KH, Hull R, Morton D, et al. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001;21(1):15–23.CrossRefPubMedGoogle Scholar
  26. 26.
    R Core Team. R: A language and environment for statistical computing, version 3.2.2. R Foundation for Statistical Computing, Vienna, Austria; 2014. http://www.R-project.org/.
  27. 27.
    Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Sobal G, Resch U, Sinzinger H. Modification of low-density lipoprotein by different radioiodination methods. Nucl Med Biol. 2004;31(3):381–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Pietzsch J, Bergmann R, Wuest F, Pawelke B, Hultsch C, van den Hoff J. Catabolism of native and oxidized low density lipoproteins: in vivo insights from small animal positron emission tomography studies. Amino Acids. 2005;29(4):389–404.CrossRefPubMedGoogle Scholar
  30. 30.
    Lougheed M, Moore ED, Scriven DR, Steinbrecher UP. Uptake of oxidized LDL by macrophages differs from that of acetyl LDL and leads to expansion of an acidic endolysosomal compartment. Arterioscler Thromb Vasc Biol. 1999;19(8):1881–90.CrossRefPubMedGoogle Scholar
  31. 31.
    Nakano A, Inoue N, Sato Y, et al. LOX-1 mediates vascular lipid retention under hypertensive state. J Hypertens. 2010;28(6):1273–80.PubMedGoogle Scholar
  32. 32.
    Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol. 2005;5(8):606–16.CrossRefPubMedGoogle Scholar
  33. 33.
    Kreissl MC, Wu HM, Stout DB, et al. Noninvasive measurement of cardiovascular function in mice with high-temporal-resolution small-animal PET. J Nucl Med. 2006;47(6):974–80.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Palanisamy GS, Kirk NM, Ackart DF, et al. Uptake and accumulation of oxidized low-density lipoprotein during mycobacterium tuberculosis infection in guinea pigs. PLoS One. 2012;7(3):e34148.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Luoto P, Laitinen I, Suilamo S, Nagren K, Roivainen A. Human dosimetry of carbon-11 labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide extrapolated from whole-body distribution kinetics and radiometabolism in rats. Mol Imaging Biol. 2010;12(4):435–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Yamada Y, Doi T, Hamakubo T, Kodama T. Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell Mol Life Sci. 1998;54(7):628–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis. 2005;182(1):1–15.CrossRefPubMedGoogle Scholar

Copyright information

© Korean Society of Nuclear Medicine 2017

Authors and Affiliations

  • Atushi Nakano
    • 1
    • 2
  • Hidekazu Kawashima
    • 1
    • 3
  • Yoshinori Miyake
    • 1
  • Tsutomu Zeniya
    • 1
    • 4
  • Akihide Yamamoto
    • 1
  • Kazuhiro Koshino
    • 1
  • Takashi Temma
    • 1
    • 5
  • Tetsuya Fukuda
    • 6
  • Yoshiko Fujita
    • 7
  • Akemi Kakino
    • 7
  • Shigehiko Kanaya
    • 8
  • Tatsuya Sawamura
    • 7
  • Hidehiro Iida
    • 1
    • 6
    • 8
  1. 1.Department of Investigative RadiologyNational Cerebral and Cardiovascular Center Research InstituteOsakaJapan
  2. 2.Department of Vascular PhysiologyNational Cerebral and Cardiovascular Center Research InstituteOsakaJapan
  3. 3.Radioisotope Research CenterKyoto Pharmaceutical UniversityKyotoJapan
  4. 4.Graduate School of Science and TechnologyHirosaki UniversityAomoriJapan
  5. 5.Department of Biofunctional AnalysisOsaka University of Pharmaceutical SciencesOsakaJapan
  6. 6.Department RadiologyNational Cerebral and Cardiovacular CenterOsakaJapan
  7. 7.Department of PhysiologyShinshu University School of MedicineNaganoJapan
  8. 8.Computational Systems Biology Laboratory, Graduate School of Information ScienceNara Institute of Science and TechonologyNaraJapan

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