Department of Colorectal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
Int J Mol Med. 2018 Nov;42(5):2849-2858. doi: 10.3892/ijmm.2018.3838. Epub 2018 Aug 23.
Radiotherapy significantly increases survival innumerous cancer patients, although it may have delayed adverse effects, including significant short‑ and long‑term effects on cardiovascular function, leading to significant morbidity and mortality. However, the mechanisms underlying these effects remain unclear. Cardiomyocyte senescence contributes to cardiovascular disease via impaired cardiac function. MicroRNA‑34a (miR‑34a) is a senescence‑associated miR involved in the pathology of cardiovascular diseases, while macrophage migration inhibitory factor (MIF) is a cardioprotective cytokine with an important role in cardiovascular diseases. The present study aimed to determine whether MIF has a cytoprotective effect in cardiomyocytes exposed to radiation through modulating miR‑34a. Human cardiomyocytes (HCMs) were incubated with MIF and then exposed to radiation. Cellular proliferation was measured using a Cell Counting Kit‑8, while cellular senescence was evaluated based on the senescence‑associated β‑galactosidase activity and the gene expression levels of cyclin‑dependent kinase inhibitor 1a (Cdkn1a) and Cdkn2c. Oxidative stress was evaluated by measuring the generation of reactive oxygen species and malondialdehyde, as well as the expression of antioxidant genes. In addition, HCMs were treated with small interfering RNA against sirtuin 1 (SIRT1) to examine the role of this gene in MIF‑associated rejuvenation following radiation‑associated senescence. miR‑34a was significantly increased in HCMs exposed to radiation, while MIF inhibited senescence by suppressing miR‑34a. SIRT1 was identified as a target gene of miR‑34a, mediating the anti‑senescence effect induced by MIF. Furthermore, MIF rejuvenation involved rebalancing the oxidation process disturbed by radiation. These results provided direct evidence that inhibition of miR‑34a by MIF protected against radiation‑induced cardiomyocyte senescence via targeting SIRT1. Inhibition of miR‑34a by MIF may thus be a novel strategy for combating cardiac radiation‑associated damage.
放射治疗显著提高了众多癌症患者的生存率，尽管它可能会产生延迟的不良反应，包括对心血管功能的重大短期和长期影响，导致重大发病率和死亡率。然而，这些影响的机制尚不清楚。心肌细胞衰老通过损害心脏功能导致心血管疾病。微小 RNA-34a (miR-34a) 是一种与心血管疾病病理相关的衰老相关 miRNA，而巨噬细胞移动抑制因子 (MIF) 是一种具有重要作用的心脏保护细胞因子在心血管疾病中。本研究旨在确定 MIF 是否通过调节 miR-34a 对暴露于辐射的心肌细胞具有细胞保护作用。将人心肌细胞 (HCM) 与 MIF 孵育，然后暴露于辐射下。使用细胞计数试剂盒-8 测量细胞增殖，同时根据衰老相关的β-半乳糖苷酶活性以及细胞周期蛋白依赖性激酶抑制剂 1a (Cdkn1a) 和 Cdkn2c 的基因表达水平评估细胞衰老。通过测量活性氧和丙二醛的产生以及抗氧化基因的表达来评估氧化应激。此外，用小干扰 RNA 处理 HCM，以研究 SIRT1 基因在辐射相关衰老后与 MIF 相关的恢复中的作用。暴露于辐射的 HCM 中 miR-34a 的表达显著增加，而 MIF 通过抑制 miR-34a 抑制衰老。SIRT1 被鉴定为 miR-34a 的靶基因，介导 MIF 诱导的抗衰老作用。此外，MIF 的恢复涉及重新平衡辐射干扰的氧化过程。这些结果提供了直接证据，表明 MIF 通过靶向 SIRT1 抑制 miR-34a 来保护心肌细胞免受辐射诱导的衰老。因此，MIF 抑制 miR-34a 可能成为对抗心脏辐射相关损伤的新策略。
