Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
Int J Mol Med. 2015 Mar;35(3):731-8. doi: 10.3892/ijmm.2014.2048. Epub 2014 Dec 24.
Radiation-induced heart disease (RIHD) is becoming an increasing concern for patients and clinicians alike due to the use of radiotherapy for the treatment of breast cancer, Hodgkin's lymphoma, pediatric cancer and tumors of the thorax. However, the mechanisms underlying this phenomenon remain largely unknown. As the senescent cell fraction following irradiation is known to increase, in the present study, we investigated whether ionizing radiation (IR) causes the onset of heart disease by inducing cellular senescence in cardiomyocytes. In the present study, we evaluated the effects of IR on HL-1 and H9C2 cells, cells predominantly used in in vitro myocardial cell models. We found that the exposure of the HL-1 and H9C2 cells to IR induced reactive oxygen species (ROS)-mediated cellular senescence, as shown by staining of senescence-associated β-galactosidase (SA-β-gal). The levels of ROS in irradiated cells were determined using the fluorescent dye, 2', 7'-dichlorodihydrofluorescein diacetate (DCF-DA). Notably, the expression of corin, a cardiac protease that is essential for the proteolytic cleavage of natriuretic peptides, was significantly decreased following the exposure of the cells to IR. Importantly, the knockdown of corin by RNA interference enhanced IR-induced senescence. On the contrary, the overexpression of natriuretic peptides reversed the IR-induced senescence. Taken together, our data suggest that defects in corin function and the inhibition of natriuretic peptides following exposure to IR may contribute to the development of RIHD through the acceleration of cellular senescence.
放射性心脏病（RIHD）是一个日益受到关注的问题，因为放射治疗被广泛用于乳腺癌、霍奇金淋巴瘤、儿科癌症和胸部肿瘤的治疗。然而，这一现象的机制在很大程度上仍然未知。已知照射后衰老细胞的比例增加，因此本研究旨在探讨电离辐射（IR）是否通过诱导心肌细胞衰老导致心脏病的发生。本研究评估了 IR 对 HL-1 和 H9C2 细胞（主要用于体外心肌细胞模型的细胞）的影响。结果表明，IR 暴露诱导 HL-1 和 H9C2 细胞产生活性氧（ROS）介导的细胞衰老，衰老相关β-半乳糖苷酶（SA-β-gal）染色显示。用荧光染料 2'，7'-二氯二氢荧光素二乙酸酯（DCF-DA）测定照射细胞中的 ROS 水平。值得注意的是，细胞暴露于 IR 后，心脏蛋白酶 corin 的表达显著降低，该酶对于利钠肽的蛋白水解切割至关重要。重要的是，corin 的 RNA 干扰敲低增强了 IR 诱导的衰老。相反，利钠肽的过表达逆转了 IR 诱导的衰老。总之，我们的数据表明，IR 暴露后 corin 功能缺陷和利钠肽抑制可能通过加速细胞衰老导致 RIHD 的发生。
