Molecular imaging of human ACE-1 expression in transgenic rats.
Academic Article
Overview
abstract
OBJECTIVES: 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.
