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PRECLINICAL STUDY

Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging

Masayoshi Sarai, MD^_*,1, Dagmar Hartung, MD^_*,,1, Artiom Petrov, PhD^_*,_*, Jun Zhou, MD^_*, Navneet Narula, MD^_*, Leo Hofstra, MD, PhD, Frank Kolodgie, PhD, Satoshi Isobe, MD^_*, Shinichiro Fujimoto, MD^_*, Jean-Luc Vanderheyden, PhD^||, Renu Virmani, MD, FACC, Chris Reutelingsperger, PhD, Nathan D. Wong, PhD^_*, Sudhir Gupta, MD, PhD^_* and Jagat Narula, MD, PhD, FACC^_*

^_* University of California, Irvine, California
Hannover Medical School, Hannover, Germany
University Hospital Maastricht, Maastricht, the Netherlands
International Registry of Pathology, Gaithersburg, Maryland
^|| Theseus Imaging Corporation, Boston, Massachusetts.

Manuscript received April 10, 2007; revised manuscript received August 23, 2007, accepted August 24, 2007.

^_* Reprint requests and correspondence: Dr. Artiom Petrov, University of California, Irvine, School of Medicine, C116 Medical Science I, Irvine, California 92697. (Email: adpetrov{at}uci.edu).

Objectives: The purpose of this study was to evaluate the role of caspase inhibitors on acute resolution of apoptosis in atherosclerotic lesions as evaluated by imaging with annexin A5.

Background: Extensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome.

Methods: Of 31 New Zealand White atherosclerotic rabbits, 6 received broad caspase, 3 received caspase-1, 3 received caspase-3, 3 received caspase-8, and 4 received caspase-9 inhibitors; 12 animals did not receive any caspase inhibitors (treatment control group). Six unmanipulated rabbits were used for comparison (disease control group). Technetium-99m–labeled annexin A5 was used for imaging atherosclerotic lesions; 6 of the 12 uninhibited atherosclerotic rabbits received ^99mTc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings.

Results: Atherosclerotic lesions were best visible in untreated atherosclerotic rabbits. Quantitative annexin uptake, defined as the percent of injected dose per g of abdominal aorta tissue, was significantly higher in untreated atherosclerotic animals (mean ± SD = 0.0515 ± 0.0099) compared with the normal rabbits (0.0065 ± 0.0008; p < 0.0001) or atherosclerotic rabbits receiving mutant annexin (0.014 ± 0.0024; p < 0.0001). Among all caspase inhibitor-treated rabbits, uptake was 39% lower (0.0314 ± 0.0151) than in untreated atherosclerotic animals (p < 0.01). Uptake was also significantly lower in rabbits receiving broad caspase (0.0206 ± 0.0058; p < 0.0001) or caspase-1, -3, or -9 (0.0272 ± 0.0088, p < 0.01; 0.0286 ± 0.0095, p < 0.01; 0.0300 ± 0.0021, p < 0.01, respectively) inhibitors. Caspase-8 inhibitor did not affect apoptosis (0.0618 ± 0.0047; p = NS). Upon histologic characterization, a substantial decrease in macrophage apoptosis was observed in caspase-inhibited animals.

Conclusions: Molecular imaging, using radiolabeled annexin A5, allows the detection of acute resolution of apoptosis as a result of caspase inhibition in experimental atherosclerosis. If proven clinically, this may allow development of novel intervention strategies in acute vascular events.

Abbreviations and Acronyms   CT = computed tomography   %ID/g = percent injected dose per gram   PS = phosphatidylserine   SPECT = single photon emission computed tomography   TUNEL = terminal deoxyribonucleotide transferase-mediated nick-end labeling

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