Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.
Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.
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通过放射性标记的膜联蛋白 A5 成像评估广泛且特异性的 caspase 抑制剂诱导的动脉粥样硬化病变细胞凋亡的急性抑制。
DOI：
10.1016/j.jacc.2007.08.044
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发表时间：
2007
影响因子：
24
通讯作者：
Narula,Jaga
中科院分区：
文献类型：
--
作者：
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,NathanD;Gupta,Sudhir;Narula,Jaga
目的本研究的目的是评估caspase抑制剂在动脉粥样硬化病变细胞凋亡急性消退中的作用，通过膜联蛋白A5成像评估。背景：据报道，急性冠脉综合征死亡患者斑块破裂部位有大量巨噬细胞凋亡。方法31只新西兰白动脉粥样硬化兔，6只给予广谱caspase， 3只给予caspase-1, 3只给予caspase-3, 3只给予caspase-8, 4只给予caspase-9抑制剂；12只动物未使用任何caspase抑制剂（治疗对照组）。6只裸兔作为对照（疾病对照组）。采用锝-99m标记的膜联蛋白A5对动脉粥样硬化病变进行成像；12只未受抑制的动脉粥样硬化兔中有6只接受了99mtc标记的突变膜联蛋白A5（放射性示踪剂对照组）。获得伽玛图像，并将定量放射性示踪剂摄取与病理结果进行比较。结果未经治疗的动脉粥样硬化家兔动脉粥样硬化病变最明显。与正常兔（0.0065±0.0008;p < 0.0001）或接受突变膜联蛋白治疗的动脉粥样硬化兔（0.014±0.0024;p < 0.0001）相比，未治疗的动脉粥样硬化动物（平均±SD = 0.0515±0.0099）的膜联蛋白定量摄取（定义为每g腹主动脉组织注射剂量的百分比）明显更高。在所有caspase抑制剂处理的家兔中，摄取比未处理的动脉粥样硬化动物低39%(0.0314±0.0151)（p < 0.01）。大剂量caspase（0.0206±0.0058,p < 0.0001）或caspase-1、-3、-9（0.0272±0.0088,p < 0.01; 0.0286±0.0095,p < 0.01; 0.0300±0.0021,p < 0.01）抑制剂的摄取也显著降低。Caspase-8抑制剂不影响细胞凋亡（0.0618±0.0047;p = NS）。根据组织学特征，在caspase抑制的动物中观察到巨噬细胞凋亡的显著减少。结论利用放射性标记的膜联蛋白A5进行分子成像，可以检测实验性动脉粥样硬化中caspase抑制导致的细胞凋亡的急性消退。如果在临床上得到证实，这可能允许开发急性血管事件的新干预策略。
ObjectivesThe 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.BackgroundExtensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome.MethodsOf 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 received99mTc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings.ResultsAtherosclerotic 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.ConclusionsMolecular 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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DOI：
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1983
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DOI：
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