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
University of California, Irvine, California.
J Am Coll Cardiol. 2007 Dec 11;50(24):2305-12. doi: 10.1016/j.jacc.2007.08.044. Epub 2007 Nov 26.
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.
Extensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome.
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 (99m)Tc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings.
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.
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.
本研究旨在通过膜联蛋白A5成像评估半胱天冬酶抑制剂在动脉粥样硬化病变中对凋亡急性消退的作用。
据报道，死于急性冠状动脉综合征的患者斑块破裂部位存在广泛的巨噬细胞凋亡。
31只新西兰白兔动脉粥样硬化模型中，6只接受广谱半胱天冬酶抑制剂，3只接受半胱天冬酶-1抑制剂，3只接受半胱天冬酶-3抑制剂，3只接受半胱天冬酶-8抑制剂，4只接受半胱天冬酶-9抑制剂；12只动物未接受任何半胱天冬酶抑制剂（治疗对照组）。6只未处理的兔子用作对照（疾病对照组）。用锝-99m标记的膜联蛋白A5对动脉粥样硬化病变进行成像；12只未抑制的动脉粥样硬化兔子中有6只接受（99m）Tc标记的突变型膜联蛋白A5（放射性示踪剂对照组）。获取γ图像，并将放射性示踪剂的定量摄取与病理结果进行比较。
未经治疗的动脉粥样硬化兔子的动脉粥样硬化病变最清晰可见。定义为每克腹主动脉组织注射剂量百分比的膜联蛋白摄取量，未经治疗的动脉粥样硬化动物（平均值±标准差=0.0515±0.0099）显著高于正常兔子（0.0065±0.0008；p<0.0001）或接受突变型膜联蛋白的动脉粥样硬化兔子（0.014±0.0024；p<0.0001）。在所有接受半胱天冬酶抑制剂治疗的兔子中，摄取量比未经治疗的动脉粥样硬化动物低39%（0.0314±0.0151）（p<0.01）。接受广谱半胱天冬酶抑制剂（0.0206±0.0058；p<0.0001）或半胱天冬酶-1、-3或-9抑制剂（分别为0.0272±0.0088，p<0.01；0.0286±0.0095，p<0.01；0.0300±0.0021，p<0.01）的兔子摄取量也显著降低。半胱天冬酶-8抑制剂不影响细胞凋亡（0.0618±0.0047；p=无显著性差异）。组织学特征显示，在半胱天冬酶抑制的动物中观察到巨噬细胞凋亡显著减少。
使用放射性标记的膜联蛋白A5进行分子成像，可以检测到实验性动脉粥样硬化中由于半胱天冬酶抑制导致的凋亡急性消退。如果在临床上得到证实，这可能有助于开发急性血管事件的新型干预策略。
