Skip to main content
Log in

In Vivo Molecular Imaging of Apoptosisand Necrosis in Atherosclerotic PlaquesUsing MicroSPECT-CT and MicroPET-CT Imaging

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this paper is to study molecular imaging of apoptosis and necrosis, two key players in atherosclerosis instability, using a multimodal imaging approach combining single photon emission computed tomography (SPECT), positron emission tomography (PET), and computed tomography (CT).

Procedures

Collar-induced carotid atherosclerosis ApoE knockout mice were imaged with 99mTc-AnxAF568 SPECT-CT to study apoptosis and sequentially with PET-CT following 124I-Hypericin (124I-Hyp) injection to visualize necrosis.

Results

SPECT depicted increased 99mTc-AnxAF568 uptake in both atherosclerotic carotid arteries, whereas our data suggest that this uptake is not merely apoptosis related. Although PET of 124I-Hyp was hampered by the slow blood clearance in atherosclerotic mice, 124I-Hyp was able to target necrosis in the atherosclerotic plaque.

Conclusion

Both 99mTc-AnxAF568 and 124I-Hyp uptake are increased in atherosclerotic carotid vasculature compared to control arteries. While apoptosis imaging remains challenging, necrosis imaging can be feasible after improving the biodistribution characteristics of the probe.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bui QT, Prempeh M, Wilensky RL (2009) Atherosclerotic plaque development. Int J Biochem Cell Biol 41(11):2109–2113

    Article  CAS  PubMed  Google Scholar 

  2. Kolodgie FD, Petrov A, Virmani R et al (2003) Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108:3134–3139

    Article  CAS  PubMed  Google Scholar 

  3. Kietselaer BL, Reutelingsperger CP, Heidendal GA et al (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 350:1472–1473

    Article  CAS  PubMed  Google Scholar 

  4. Tait JF, Smith C, Blankenberg FG (2005) Structural requirements for in vivo detection of cell death with 99mTc-annexin V. J Nucl Med 46(5):807–815

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Bauwens M, De Saint-Hubert M, Devos E et al (2011) Site-specific 68Ga-labeled Annexin A5 as a PET imaging agent for apoptosis. Nucl Med Biol 38:381–392

    Article  CAS  PubMed  Google Scholar 

  6. De Saint-Hubert M, Mottaghy FM, Vunckx K et al (2010) Site-specific labeling of ‘second generation’ annexin V with 99mTc(CO)3 for improved imaging of apoptosis in vivo. Bioorg Med Chem 18:1356–1363

    Article  PubMed  Google Scholar 

  7. Bauwens M, De Saint-Hubert M, Cleynhens J et al (2013) In vitro and in vivo comparison of 18F and 123I-labeled ML10 with 68Ga-Cys2-AnxA5 for molecular imaging of apoptosis. Q J Nucl Med Mol Imaging 57:187–200

    CAS  PubMed  Google Scholar 

  8. De Saint-Hubert M, Wang H, Devos E et al (2010) Preclinical imaging of therapy response using metabolic and apoptosis molecular imaging. Mol Imaging Biol 13:995–1002

    Article  Google Scholar 

  9. Fonge H, de Saint HM, Vunckx K et al (2008) Preliminary in vivo evaluation of a novel 99mTc-labeled HYNIC-cys-annexin A5 as an apoptosis imaging agent. Bioorg Med Chem Lett 18:3794–3798

    Article  CAS  PubMed  Google Scholar 

  10. Tait JF, Smith C, Levashova Z et al (2006) Improved detection of cell death in vivo with annexin V radiolabeled by site-specific methods. J Nucl Med 47:1546–1553

    CAS  PubMed  Google Scholar 

  11. Galluzzi L, Vitale I, Abrams JM et al (2011) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120

    Article  PubMed Central  PubMed  Google Scholar 

  12. Martinet W, Schrijvers DM, De Meyer GR (2011) Necrotic cell death in atherosclerosis. Basic Res Cardiol 106:749–760

    Article  CAS  PubMed  Google Scholar 

  13. De Saint-Hubert M, Prinsen K et al (2009) Molecular imaging of cell death. Methods 48(2):178–187

    Article  PubMed  Google Scholar 

  14. Fonge H, Van de Putte M, Huyghe D, Bormans G, Ni Y, de Witte P et al (2007) Evaluation of tumor affinity of mono-[(123)I]iodohypericin and mono-[(123)I]iodoprotohypericin in a mouse model with a RIF-1 tumor. Contrast Media Mol Imaging 2:113–119

    Article  CAS  PubMed  Google Scholar 

  15. Van de Putte M, Marysael T, Fonge H et al (2011) Radiolabeled iodohypericin as tumor necrosis avid tracer: diagnostic and therapeutic potential. Int J Cancer 131:E129–E137

    Article  Google Scholar 

  16. von der Thusen JH, van Berkel TJ, Biessen EA (2001) Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Circulation 103:1164–1170

    Article  PubMed  Google Scholar 

  17. Ku DN, Giddens DP, Zarins CK, Glagov S (1985) Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis 5:293–302

    Article  CAS  PubMed  Google Scholar 

  18. Topper JN, Gimbrone MA Jr (1999) Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol Med Today 5:40–46

    Article  CAS  PubMed  Google Scholar 

  19. Golledge J, Turner RJ, Harley SL et al (1997) Circumferential deformation and shear stress induce differential responses in saphenous vein endothelium exposed to arterial flow. J Clin Invest 99:2719–2726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Nakashima Y, Plump AS, Raines EW et al (1994) ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140

    Article  CAS  PubMed  Google Scholar 

  21. Lievens D, Gerdes N, Schober A, Weber C (2010) Atherosclerosis: cell biology and lipoproteins. Curr Opin Lipidol 21:284–285

    Article  CAS  PubMed  Google Scholar 

  22. Lievens D, Zernecke A, Seijkens T et al (2010) Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 116:4317–4327

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Thorp E, Li G, Seimon TA et al (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab 9:474–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Isobe S, Tsimikas S, Zhou J et al (2006) Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5. J Nucl Med 47:1497–1505

    CAS  PubMed  Google Scholar 

  25. Zhao Y, Kuge Y, Zhao S et al (2008) Prolonged high-fat feeding enhances aortic 18F-FDG and 99mTc-annexin A5 uptake in apolipoprotein E-deficient and wild-type C57BL/6J mice. J Nucl Med 49:1707–1714

    Article  PubMed  Google Scholar 

  26. van Tilborg GA, Vucic E, Strijkers GJ et al (2010) Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques. Bioconjug Chem 21:1794–1803

    Article  PubMed Central  PubMed  Google Scholar 

  27. Ding SF, Ni M, Liu XL et al (2010) A causal relationship between shear stress and atherosclerotic lesions in apolipoprotein E knockout mice assessed by ultrasound biomicroscopy. Am J Physiol Heart Circ Physiol 298:H2121–H2129

    Article  CAS  PubMed  Google Scholar 

  28. Kenis H, Zandbergen HR, Hofstra L et al (2010) Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging. J Nucl Med 51:259–267

    Article  CAS  PubMed  Google Scholar 

  29. Hartung D, Sarai M, Petrov A et al (2005) Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. J Nucl Med 46:2051–2056

    CAS  PubMed  Google Scholar 

  30. Bormans G, Huyghe D, Christiaen A et al (2004) Preparation, analysis and biodistribution in mice of iodine-123 labelled derivatives of hypericin. J Label Compd Radiopharm 47:191–198

    Article  CAS  Google Scholar 

  31. Lavie G, Mazur Y, Lavie D, Meruelo D (1995) The chemical and biological properties of hypericin—a compound with a broad spectrum of biological activities. Med Res Rev 15:111–119

    Article  CAS  PubMed  Google Scholar 

  32. Prinsen K, Li J, Vanbilloen H, Vermaelen P et al (2010) Development and evaluation of a 68Ga labeled pamoic acid derivative for in vivo visualization of necrosis using positron emission tomography. Bioorg Med Chem 18:5274–5281

    Article  CAS  PubMed  Google Scholar 

  33. Phinikaridou A, Andia ME, Shah AM, Botnar RM (2012) Advances in molecular imaging of atherosclerosis and myocardial infarction: shedding new light on in vivo cardiovascular biology. Am J Physiol Heart Circ Physiol 303:H1397–H1410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded by the CTMM project 01C-204-03 EMINENCE and the Weijerhorst project. We would also like to acknowledge Christian Urbach and Ans Houben for their technical support in this study.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. De Saint-Hubert.

Additional information

M. De Saint-Hubert and M. Bauwens contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 2.52 MB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Saint-Hubert, M., Bauwens, M., Deckers, N. et al. In Vivo Molecular Imaging of Apoptosisand Necrosis in Atherosclerotic PlaquesUsing MicroSPECT-CT and MicroPET-CT Imaging. Mol Imaging Biol 16, 246–254 (2014). https://doi.org/10.1007/s11307-013-0677-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-013-0677-0

Key words

Navigation