Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays.
Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays.
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DOI：
10.1371/journal.pone.0027811
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Tapio S
中科院分区：
文献类型：
--
作者：
Barjaktarovic Z;Schmaltz D;Shyla A;Azimzadeh O;Schulz S;Haagen J;Dörr W;Sarioglu H;Schäfer A;Atkinson MJ;Zischka H;Tapio S
乳腺癌、霍奇金病或儿童癌症的放射治疗使心脏暴露于高局部辐射剂量，导致治疗数十年后幸存者患心血管疾病的风险增加。到目前为止，对辐射损伤的机制仍然知之甚少。先前的数据表明，线粒体氧化代谢的损伤与心血管疾病的发展直接相关。在这项研究中，辐射诱导的心脏线粒体蛋白质组和功能的体内效应进行了研究。C57 BL/6 N小鼠在8周龄时接受0.2戈伊或2戈伊（X射线，200 kV）的心脏局部照射，对照小鼠接受假照射。四周后，分离心肌线粒体并测试蛋白质组学和功能改变。两个互补的蛋白质组学方法，使用肽和蛋白质定量策略显示辐射诱导的失调的25种蛋白质。三个主要的生物类别受到影响：氧化磷酸化，丙酮酸代谢，和细胞骨架结构。暴露于高剂量辐射的线粒体表现出功能损伤，反映为复合物I（32%）和复合物III（11%）的部分失活，琥珀酸驱动的呼吸能力下降（13%），活性氧水平增加和线粒体蛋白质氧化增强。丙酮酸代谢和结构蛋白的变化与低和高辐射剂量。这是第一项研究表明，在暴露于低剂量和高剂量电离辐射数周后，小鼠心脏线粒体发生了生物学变化。我们的研究结果表明，剂量，相当于一个单一剂量的放射治疗，导致长期持久的变化，线粒体氧化代谢和线粒体相关的细胞骨架。这促使我们提出，这些最初的病理变化导致辐射暴露后心血管疾病的风险增加。
Radiation therapy treatment of breast cancer, Hodgkin's disease or childhood cancers expose the heart to high local radiation doses, causing an increased risk of cardiovascular disease in the survivors decades after the treatment. The mechanisms that underlie the radiation damage remain poorly understood so far. Previous data show that impairment of mitochondrial oxidative metabolism is directly linked to the development of cardiovascular disease. In this study, the radiation-induced in vivo effects on cardiac mitochondrial proteome and function were investigated. C57BL/6N mice were exposed to local irradiation of the heart with doses of 0.2 Gy or 2 Gy (X-ray, 200 kV) at the age of eight weeks, the control mice were sham-irradiated. After four weeks the cardiac mitochondria were isolated and tested for proteomic and functional alterations. Two complementary proteomics approaches using both peptide and protein quantification strategies showed radiation-induced deregulation of 25 proteins in total. Three main biological categories were affected: the oxidative phophorylation, the pyruvate metabolism, and the cytoskeletal structure. The mitochondria exposed to high-dose irradiation showed functional impairment reflected as partial deactivation of Complex I (32%) and Complex III (11%), decreased succinate-driven respiratory capacity (13%), increased level of reactive oxygen species and enhanced oxidation of mitochondrial proteins. The changes in the pyruvate metabolism and structural proteins were seen with both low and high radiation doses. This is the first study showing the biological alterations in the murine heart mitochondria several weeks after the exposure to low- and high-dose of ionizing radiation. Our results show that doses, equivalent to a single dose in radiotherapy, cause long-lasting changes in mitochondrial oxidative metabolism and mitochondria-associated cytoskeleton. This prompts us to propose that these first pathological changes lead to an increased risk of cardiovascular disease after radiation exposure.
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