This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2007.08.044v1 50/24/2305    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarai, M. Articles by Narula, J. Search for Related Content PubMed Articles by Sarai, M. Articles by Narula, J.

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

This article has been cited by other articles:

				J. Narula and V. Dilsizian From Better Understood Pathogenesis to Superior Molecular Imaging, and Back... J. Am. Coll. Cardiol. Img., May 1, 2008; 1(3): 406 - 409. [Full Text] [PDF]