title: Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy.
abstract: OBJECTIVE
  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.
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fujimoto
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hartung
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Satoru
authors.initials: S
authors.lastname: Ohshima
authors.affiliation: Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Edwards
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Yalamanchili
authors.affiliation: Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Ai
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Isobe
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: University Medical Center, Groningen, the Netherlands.
authors.forename: Hendricus
authors.initials: H
authors.lastname: Boersma
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Nathan
authors.initials: N
authors.lastname: Wong
authors.affiliation: Toho University School of Medicine, Ohmori Hospital, Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Yamazaki
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California. Electronic address: adpetrov@uci.edu.
authors.forename: Artiom
authors.initials: A
authors.lastname: Petrov
authors.affiliation: University of California, Irvine School of Medicine, Irvine, California.
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D050197:Atherosclerosis / Q000178:diet therapy* / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D011817:Rabbits; D013667:Technetium / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013667:Technetium; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9