title: Molecular imaging of human ACE-1 expression in transgenic rats.
abstract: OBJECTIVE
  The aim of this study was to develop a molecular imaging strategy that can monitor myocardial angiotensin-converting enzyme (ACE)-1 upregulation as a function of progressive heart failure.
  
  
  BACKGROUND
  High-affinity technetium-99m-labeled lisinopril (Tc-Lis) has been shown to specifically localize in tissues that express ACE in vivo, such as the lungs. Whether Tc-Lis can also detect upregulation of ACE in the heart, by external in vivo imaging, has not been established.
  
  
  METHODS
  Twenty-one ACE-1 over-expressing transgenic (Tg) and 18 wild-type control rats were imaged using in vivo micro single-positron emission computed tomography (SPECT)-computed tomography (CT) at 10, 30, 60, and 120 min after Tc-Lis injection. A subgroup of rats received nonradiolabeled (cold) lisinopril before the Tc-Lis injection to evaluate nonspecific binding. After imaging, the rat myocardium was explanted, ex vivo images were acquired, and percent injected dose per gram gamma-well was counted, followed by an assessment of enzyme-linked immunosorbent assay-verified ACE activity and messenger ribonucleic acid expression.
  
  
  RESULTS
  On micro SPECT-CT, myocardial ACE-1 uptake was best visualized in Tg rats at 120 min after Tc-Lis injection. The quantitative uptake of Tc-Lis in the myocardium was 5-fold higher in mutant Tg than in control rats at each time point after tracer injection. The percent injected dose per gram uptake was 0.74 ± 0.13 in Tg myocardium at 30 min and was reduced substantially to 0.034 ± 0.003% when pre-treated with cold lisinopril (p = 0.029). Enzyme activity assay showed a >30-fold higher level of ACE-1 activity in the myocardium of Tg rats than in controls. The ACE-1 messenger ribonucleic acid was quantified, and lisinopril was found to have no effect on ACE-1 gene expression.
  
  
  CONCLUSIONS
  The Tc-Lis binds specifically to ACE, and the activity can be localized in Tg rat hearts that over-express human ACE-1 with a signal intensity that is sufficiently high to allow external imaging. Such a molecular imaging strategy may help identify susceptibility to heart failure and may allow optimization of pharmacologic intervention.
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. vdilsizian@umm.edu
authors.forename: Vasken
authors.initials: V
authors.lastname: Dilsizian
authors.forename: Todd K
authors.initials: TK
authors.lastname: Zynda
authors.forename: Artiom
authors.initials: A
authors.lastname: Petrov
authors.forename: Satoru
authors.initials: S
authors.lastname: Ohshima
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tahara
authors.forename: Nezam
authors.initials: N
authors.lastname: Haider
authors.forename: Amanda
authors.initials: A
authors.lastname: Donohue
authors.forename: Omer
authors.initials: O
authors.lastname: Aras
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Femia
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Wong
authors.forename: Tomika
authors.initials: T
authors.lastname: Coleman
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
mesh_terms: D000818:Animals; D055426:Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography / Q000379:methods*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009206:Myocardium / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012313:RNA / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D012313:RNA; D007703:Peptidyl-Dipeptidase A