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Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions
Open accessAbstract
Objectives This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m-labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity.Background The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture.Methods Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro-single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays.Results The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 +/- 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 +/- 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 +/- 0.011%, p < 0.0005) and diet withdrawal groups (0.043 +/- 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques.Conclusions The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.
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“To detect different aspects of atherosclerotic disease more specifically, various radioactive tracers have been developed145–147.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [145]
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Metadata
- Authors
- Fujimoto, S., Hartung, D., Ohshima, S., Edwards, D. S., Zhou, J., Yalamanchili, P., Azure, M., Fujimoto, A., Isobe, S., Matsumoto, Y., Boersma, H., Wong, N., Yamazaki, J., Narula, N., Petrov, A., & Narula, J.
- Affiliations
- University of California, Irvine (US)
- Bristol-Myers Squibb (United States) (US)
- Toho University (JP)
- Corresponding author
- Petrov, Artiom
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 52
- Issue
- 23
- Pages
- 1847-1857
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2141910805
- Cited by
- 133
- References
- 42
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 10 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 10 · 2016: 2 · 2015: 6 · 2014: 16 · 2013: 8 · 2012: 11
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (R01HL078681)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- matrix metalloproteinases, atherosclerosis, MMP-2, MMP-9, plaque vulnerability, macrophage infiltration, fluvastatin, statin therapy, high-cholesterol diet, rabbit model, atherosclerotic plaque imaging, radiotracer clearance
- MeSH terms
- Animals, Aorta, Abdominal, Combined Modality Therapy, Immunohistochemistry, Macrophages, Male, Models, Chemical, Rabbits, Technetium, Tomography, Emission-Computed, Single-Photon, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Atherosclerosis, Matrix Metalloproteinase Inhibitors
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