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

Masayoshi Sarai, Dagmar Hartung, Artiom Petrov, Jun Zhou, Navneet Narula, Leo Hofstra, Frank Kolodgie, Satoshi Isobe, Shinichiro Fujimoto, Jean Luc Vanderheyden, Renu Virmani, Chris Reutelingsperger, Nathan D. Wong, Sudhir Gupta, Jagat Narula

研究成果: Article

42 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)2305-2312
ページ数8
ジャーナルJournal of the American College of Cardiology
50
発行部数24
DOI
出版物ステータスPublished - 11-12-2007
外部発表Yes

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Caspase Inhibitors
Annexin A5
Apoptosis
Rabbits
Caspase 3
Caspases
Annexins
Caspase 1
Caspase 8
Control Groups
Macrophages
Molecular Imaging
Caspase 9
Abdominal Aorta
Technetium
Acute Coronary Syndrome
Blood Vessels
Rupture
Atherosclerosis

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Sarai, Masayoshi ; Hartung, Dagmar ; Petrov, Artiom ; Zhou, Jun ; Narula, Navneet ; Hofstra, Leo ; Kolodgie, Frank ; Isobe, Satoshi ; Fujimoto, Shinichiro ; Vanderheyden, Jean Luc ; Virmani, Renu ; Reutelingsperger, Chris ; Wong, Nathan D. ; Gupta, Sudhir ; Narula, Jagat. / Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging. :: Journal of the American College of Cardiology. 2007 ; 巻 50, 番号 24. pp. 2305-2312.
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title = "Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging",
abstract = "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.",
author = "Masayoshi Sarai and Dagmar Hartung and Artiom Petrov and Jun Zhou and Navneet Narula and Leo Hofstra and Frank Kolodgie and Satoshi Isobe and Shinichiro Fujimoto and Vanderheyden, {Jean Luc} and Renu Virmani and Chris Reutelingsperger and Wong, {Nathan D.} and Sudhir Gupta and Jagat Narula",
year = "2007",
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language = "English",
volume = "50",
pages = "2305--2312",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
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Sarai, M, Hartung, D, Petrov, A, Zhou, J, Narula, N, Hofstra, L, Kolodgie, F, Isobe, S, Fujimoto, S, Vanderheyden, JL, Virmani, R, Reutelingsperger, C, Wong, ND, Gupta, S & Narula, J 2007, 'Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging', Journal of the American College of Cardiology, 巻. 50, 番号 24, pp. 2305-2312. https://doi.org/10.1016/j.jacc.2007.08.044

Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging. / Sarai, Masayoshi; Hartung, Dagmar; Petrov, Artiom; Zhou, Jun; Narula, Navneet; Hofstra, Leo; Kolodgie, Frank; Isobe, Satoshi; Fujimoto, Shinichiro; Vanderheyden, Jean Luc; Virmani, Renu; Reutelingsperger, Chris; Wong, Nathan D.; Gupta, Sudhir; Narula, Jagat.

:: Journal of the American College of Cardiology, 巻 50, 番号 24, 11.12.2007, p. 2305-2312.

研究成果: Article

TY - JOUR

T1 - Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging

AU - Sarai, Masayoshi

AU - Hartung, Dagmar

AU - Petrov, Artiom

AU - Zhou, Jun

AU - Narula, Navneet

AU - Hofstra, Leo

AU - Kolodgie, Frank

AU - Isobe, Satoshi

AU - Fujimoto, Shinichiro

AU - Vanderheyden, Jean Luc

AU - Virmani, Renu

AU - Reutelingsperger, Chris

AU - Wong, Nathan D.

AU - Gupta, Sudhir

AU - Narula, Jagat

PY - 2007/12/11

Y1 - 2007/12/11

N2 - 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.

AB - 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.

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