title: Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation.
abstract: Matrix metalloproteinases (MMPs) play a key role in the development of atherosclerosis and its complications. In vivo detection and quantification of MMP activation can help track the propensity to complications and response to therapy. We sought to establish an in vivo imaging approach for monitoring MMP activation in atherosclerotic mouse aorta and use it to assess the response to dietary modification.
  
  
  METHODS
  Apolipoprotein-deficient mice were fed normal chow or a high-fat diet (HFD) for up to 3 mo or a HFD for 2 mo, followed by 1 mo on normal chow. Then they underwent micro-SPECT/CT, along with autoradiography and oil red O staining of tissues.
  
  
  RESULTS
  After 3 mo of HFD, there was considerable atherosclerosis in the aorta. In vivo micro-SPECT/CT using RP782 (an (111)In-labeled tracer targeting activated MMPs) showed a heterogeneous pattern of tracer uptake along the aorta. Heterogeneity of RP782 uptake was confirmed by autoradiography, and specificity was demonstrated using excess unlabeled precursor. Tracer uptake quantified by micro-SPECT significantly correlated with uptake quantified by autoradiography. Comparison of oil red O staining with autoradiography demonstrated areas of discordance between plaque presence and tracer uptake. HFD withdrawal led to significant reduction in RP782 uptake beyond the effect on plaque area. MMP expression and macrophage infiltration were similarly heterogeneous along the aorta and significantly reduced after withdrawal from the HFD. Finally, RP782 uptake significantly correlated with aortic macrophage content.
  
  
  CONCLUSIONS
  Molecular imaging of MMP activation reveals the heterogeneity of atherosclerotic plaques and is a useful tool for tracking plaque biology and response to therapy.
authors.affiliation: Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Razavian
authors.forename: Sina
authors.initials: S
authors.lastname: Tavakoli
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Dobrucki
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Sinusas
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.forename: Simon
authors.initials: S
authors.lastname: Robinson
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
mesh_terms: D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D001692:Biological Transport; D059305:Diet, High-Fat / Q000009:adverse effects; D004789:Enzyme Activation; D005260:Female; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging; D064847:Multimodal Imaging; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D001057:Apolipoproteins E; D011849:Radioactive Tracers; D020782:Matrix Metalloproteinases