title: Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with (99m)Tc-labeled matrix metalloproteinase inhibitor (MPI) and (111)In-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Cardiology, Irvine School of Medicine, University of California, C116 Med Sci I, Irvine, CA 92697, USA.
authors: Nezam
authors: N
authors: Haider
authors: Dagmar
authors: D
authors: Hartung
authors: Shinichiro
authors: S
authors: Fujimoto
authors: Artiom
authors: A
authors: Petrov
authors: Frank D
authors: FD
authors: Kolodgie
authors: Renu
authors: R
authors: Virmani
authors: Satoru
authors: S
authors: Ohshima
authors: Han
authors: H
authors: Liu
authors: Jun
authors: J
authors: Zhou
authors: Ai
authors: A
authors: Fujimoto
authors: Atsuko
authors: A
authors: Tahara
authors: Leo
authors: L
authors: Hofstra
authors: Navneet
authors: N
authors: Narula
authors: Chris
authors: C
authors: Reutelingsperger
authors: Jagat
authors: J
authors: Narula
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000201:enzymology* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D015336:Molecular Probe Techniques; D011817:Rabbits; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D011868:Radioisotopes; D019275:Radiopharmaceuticals; D020782:Matrix Metalloproteinases