title: Noninvasive monitoring the biology of atherosclerotic plaque development with radiolabeled annexin V and matrix metalloproteinase inhibitor in spontaneous atherosclerotic mice.
abstract: OBJECTIVE
  To compare the ability of (99m)Tc-labeled broad-based matrix metalloproteinase inhibitor (RP805) (MPI) and (99m)Tc-annexin V to identify more advanced atherosclerotic disease in apolipoprotein E-null (apoE(-/-)) mice.
  
  
  BACKGROUND
  Both MMP expression and apoptotic cell death occur in both early and in advanced atherosclerotic plaques.
  
  
  METHODS
  Eight 6-9-week-old apoE(-/-) mice, 10 apoE(-/-) mice at 20 weeks, and 12 apoE(-/-) at 40 weeks were injected with both tracers in alternating sequence separated by 48 h, underwent planar imaging and were killed. Radiotracer uptake was quantified from the scans as percent whole body and from tissue as percent injected dose per gram (%ID/g). Quantitative immunohistopathology of the aorta and carotids for macrophages, MMPs, and caspase was performed.
  
  
  RESULTS
  At 6 weeks, mice showed no tracer uptake in the chest or neck and had minimal lesion. At 20 weeks, uptake of annexin V as %ID was borderline higher than MPI (1.10 ± .48% vs .77 ± .31%, P = .09), between 20 and 40 weeks aortic lesion area increased from 37.4 ± 12.0% to 46.2 ± 7.4% and at 40 weeks MPI was significantly greater than annexin V uptake (1.11 ± .66% vs .70 ± .16%, P = .05). On histology there were greater increases in % MMP-2 and -9 than % caspase positive cells. Carotid uptake of MPI was greater than annexin V at both 20 and 40 weeks (1.25 ± .48% vs .78 ± .25%, P = .02 and 3.70 ± 1.45% vs 2.25 ± .66%, P = .005). The carotid lesion area at 40 weeks was 74 ± 9% with greater % cells positive for MMP's than caspase. %ID/g annexin V correlated significantly with % macrophages and with caspase-3 positive cells and %ID/g MPI correlated significantly with % macrophages and with MMP-2 and -9 positive cells.
  
  
  CONCLUSIONS
  In apoE(-/-) mice, MMP expression is greater than apoptosis as the disease progresses and MPI may be a better imaging agent for more advanced disease.
authors.affiliation: Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. yt2166@columbia.edu
authors.forename: Yared
authors.initials: Y
authors.lastname: Tekabe
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Joane
authors.initials: J
authors.lastname: Luma
authors.forename: Drew
authors.initials: D
authors.lastname: Weisenberger
authors.forename: Marija
authors.initials: M
authors.lastname: Sedlar
authors.forename: Evis
authors.initials: E
authors.lastname: Harja
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
authors.forename: Lynne L
authors.initials: LL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000175:diagnosis* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D013667:Technetium / Q000494:pharmacology; D013997:Time Factors
chemical_list: D017304:Annexin A5; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013667:Technetium