Cited by 133Protease and Inhibitor MechanismsCardiac Imaging and DiagnosticsCerebrovascular and Carotid Artery Diseases

Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions

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Fujimoto, Shinichiro, Hartung, Dagmar, Ohshima, Satoru, Edwards, D. Scott, Zhou, Jun, Yalamanchili, Padmaja, Azure, Michael, Fujimoto, Ai +8 more·2008·Journal of the American College of Cardiology

Abstract

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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Crossref · 10.1016/j.jacc.2008.08.048

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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
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 › Pulmonary and Respiratory 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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