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

Abstract

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.

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

“…Moreover, its expression is under the control of p53 oncoprotein, which is induced by ionizing radiation [78]. Moreover, as previously described, miR-34a modulates ROS and inflammation production; in keeping, the migration inhibitory factor (MIF) cardio-protective cytokine was shown to decrease miR-34a levels in human cardiomyocytes exposed to ionizing radiation, reducing the radiation-associated senescence through the up-regulation of the miR-34a protein target SIRT1 [77].…”

“…miR-34a was also shown to be up-regulated in human cardiomyocytes exposed to radiation [77]. miR-34a is of great interest in radiobiology, since it plays different roles in radiation response.…”

Exosomal LncRNA–NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p

“…Brie y, the cells at the density of 2 × 10 4 were xed with 2% paraformaldehyde and incubated with the SAβ-gal staining solution as previously described [26].…”

Emerging Challenges of Radiation-Associated Cardiovascular Dysfunction (RACVD) in Modern Radiation Oncology: Clinical Practice, Bench Investigation, and Multidisciplinary Care

“…For example, IR may impair corin function and inhibit natriuretic peptides to accelerate senescence of cardiac and endothelial cells, contributing to the development of RACVD (151). Besides, several pathways have been identified with involvement into the process of RACVD, such as the 5lipoxygenase (5-LO)/leukotriene pathway (152), the miRNA-34a/sirtuin-1 signaling pathway (149), the Reactive Oxygen Species (ROS)-mediated p16 pathway (153), and the TGF-βassociated signaling (154).…”

“…For instance, applying miR-126-5p therapy potentially improves endothelial recovery and prevents post-irradiation vascular re-stenosis (55). Besides, inhibiting miR34a by macrophage migration inhibitory factor (MIF) has been reported to reduce radiation-induced cardiomyocyte senescence via targeting SIRT1, implicating a novel strategy for managing RACVD (149). Moreover, molecular hydrogen, i.e., hydrogen-rich water (HRW; H 2 water), shows protective effects on IR-induced heart damage via regulating miRNA-1, -15b, and -21 (52).…”