Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions. Resolution With Dietary Modification and Statin Therapy

Shinichiro Fujimoto, Dagmar Hartung, Satoru Ohshima, D. Scott Edwards, Jun Zhou, Padmaja Yalamanchili, Michael Azure, Ai Fujimoto, Satoshi Isobe, Yuji Matsumoto, Hendricus Boersma, Nathan Wong, Junichi Yamazaki, Navneet Narula, Artiom Petrov, Jagat Narula

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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.

Original languageEnglish
Pages (from-to)1847-1857
Number of pages11
JournalJournal of the American College of Cardiology
Volume52
Issue number23
DOIs
StatePublished - 2 Dec 2008
Externally publishedYes

Keywords

  • HMG coenzyme reductase inhibitor
  • atherosclerosis
  • matrix metalloproteinase
  • molecular imaging

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