Molecular Imaging of Human ACE-1 Expression in Transgenic Rats

JACC-CARDIOVASCULAR IMAGING

卷:5

Article

Dilsizian, Vasken¹  Zynda, Todd K.²  Petrov, Artiom⁴  Ohshima, Satoru²  Tahara, Nobuhiro²  Haider, Nezam⁴  Donohue, Amanda²  Femia, Frank J.³  Hillier, Shawn M.³  Joyal, John L.³  Wong, Nathan D.²  Babich, John W.³  Narula, Jagat⁴ 

[1] Univ Maryland, Med Ctr, Dept Diagnost Radiol & Nucl Med, Sch Med, Baltimore, MD 21201 USA

[2] Univ Calif Irvine, Div Cardiol, Irvine, CA USA

[3] Mol Insight Pharmaceut, Cambridge, MA USA

[4] Mt Sinai Sch Med, Zena & Michael A Weiner Cardiovasc Inst, New York, NY USA

关键词: angiotensin-converting enzyme;    heart failure;    lisinopril;    radionuclide imaging;    remodeling;    SPECT-CT;   

DOI  :  10.1016/j.jcmg.2011.10.008

来源: Elsevier

【 摘 要 】

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-I 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. (J Am Coll Cardiol 'mg 2012;5:409-18) (C) 2012 by the American College of Cardiology Foundation

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