Macrophage migration inhibitory factor serves a pivotal role in the regulation of radiation-induced cardiac senescence through rebalancing the microRNA-34a/sirtuin 1 signaling pathway

摘要

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 cardio-protective 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 -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.