Molecular Imaging of Human ACE-1 Expression in Transgenic Rats

• Published in: JACC. Cardiovascular imaging Vol. 5; no. 4; pp. 409 - 418
• Main Authors: Dilsizian, Vasken, MD, Zynda, Todd K., DO, Petrov, Artiom, PhD, Ohshima, Satoru, MD, PhD, Tahara, Nobuhiro, MD, PhD, Haider, Nezam, PhD, Donohue, Amanda, DO, Aras, Omer, MD, Femia, Frank J., PhD, Hillier, Shawn M., PhD, Joyal, John L., PhD, Wong, Nathan D., PhD, Coleman, Tomika, MS, Babich, John W., PhD, Narula, Jagat, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States 01-04-2012
• Subjects: Animals; Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography - methods; Cardiovascular; Disease Models, Animal; Gene Expression Regulation; Heart Failure - diagnostic imaging; Heart Failure - enzymology; Heart Failure - genetics; Humans; Myocardium - enzymology; Peptidyl-Dipeptidase A - biosynthesis; Peptidyl-Dipeptidase A - genetics; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA - analysis; Up-Regulation; computed tomography; heart failure; remodeling; ACE; cardiac deoxyribonucleic acid; Tc-Lis; percent injected dose per gram; mRNA; SPECT-CT; SPECT; lisinopril; CT; ID/g; technitium-99m–labeled lisinopril; Tg; single-positron emission computed tomography; radionuclide imaging; messenger ribonucleic acid; cDNA; transgenic; positron emission tomography; PET; angiotensin-converting enzyme
• ISSN: 1936-878X; 1876-7591
• DOI: 10.1016/j.jcmg.2011.10.008

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.