Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation.
Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation.
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DOI：
10.1667/rr1948.1
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发表时间：
2010-06
影响因子：
3.4
通讯作者：
Braunhut SJ
中科院分区：
文献类型：
--
作者：
Vorotnikova E;Rosenthal RA;Tries M;Doctrow SR;Braunhut SJ
许多体外和体内研究表明，肺和肾的微血管内皮细胞因暴露于电离辐射而受损，这种持续的内皮细胞损伤与在这些组织中观察到的早期和晚期辐射效应有关。普遍认为电离辐射在照射过程中会导致活性氧物质的产生，从而导致DNA和细胞器的损伤。然而，更有争议的是，是否会发生额外的生化事件或长寿命的自由基，并在辐射后持续存在，从而放大并引发新形式的细胞损伤。合成了两类具有超氧化物歧化酶（SOD）、过氧化氢酶和过氧化物酶活性的Eukarion（EUK）化合物。锰卟啉可口服，而salen锰络合物通过注射给药。在本研究中，我们研究了这些SOD/过氧化氢酶模拟物的能力，以防止内皮细胞凋亡时，给药postirradiation（缓解）。用Salen锰配合物（EUK-189和EUK-207）和锰卟啉（EUK-418、-423、-425、-450、-451、-452、-453）处理体外培养的内皮细胞，在细胞接受2-20戈伊电离辐射后1 h，观察其对内皮细胞增殖的影响。两种先导化合物，剂量为30 μM的EUK-207和剂量为10 μM的EUK-451，表现出低毒性并减轻辐射诱导的细胞凋亡。未来的动物研究将测试这些化合物在辐射暴露后给药时是否具有保护作用，就像在辐射事故或恐怖主义事件后所做的那样。
Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2–20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 μM and EUK-451 at a dose of 10 μM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event.