Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis
- Nezam Haider PhD,
- Dagmar Hartung MD,
- Shinichiro Fujimoto MD, PhD,
- Artiom Petrov PhD,
- Frank D. Kolodgie PhD,
- Renu Virmani MD,
- Satoru Ohshima MD, PhD,
- Han Liu MS,
- Jun Zhou MD,
- Ai Fujimoto MD,
- Atsuko Tahara MD,
- Leo Hofstra MD,
- Navneet Narula MD,
- Chris Reutelingsperger PhD,
- Jagat Narula MD, PhD
- … show all 15 hide
Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.
Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with 99mTc-labeled matrix metalloproteinase inhibitor (MPI) and 111In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.
MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 ± .018%) and AA5 (.03 ± .01%) uptake was higher in HC than control (n = 6) animals (.014 ± .004%, P < .0001; .0007 ± .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.
The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.
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- Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis
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Journal of Nuclear Cardiology
Volume 16, Issue 5 , pp 753-762
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- vulnerable atherosclerotic plaque
- Industry Sectors
- Nezam Haider PhD (1)
- Dagmar Hartung MD (1)
- Shinichiro Fujimoto MD, PhD (1)
- Artiom Petrov PhD (1)
- Frank D. Kolodgie PhD (2)
- Renu Virmani MD (2)
- Satoru Ohshima MD, PhD (1)
- Han Liu MS (1)
- Jun Zhou MD (1)
- Ai Fujimoto MD (1)
- Atsuko Tahara MD (1)
- Leo Hofstra MD (3)
- Navneet Narula MD (4)
- Chris Reutelingsperger PhD (5)
- Jagat Narula MD, PhD (1)
- Author Affiliations
- 1. Department of Cardiology, Irvine School of Medicine, University of California, C116 Med Sci I, Irvine, CA, 92697, USA
- 2. Cardiovascular Pathology Institute, Gaithersburg, MD, USA
- 3. Department of Cardiology, University Hospital Maastricht, Academic University of Maastricht, Maastricht, The Netherlands
- 4. Department of Pathology, Irvine School of Medicine, University of California, C116 Med Sci I, Irvine, CA, 92697, USA
- 5. Department of Biochemistry, University Hospital Maastricht, Academic University of Maastricht, Maastricht, The Netherlands