Abstract
BackgroundThe chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC.ResultsExosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated β-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA–NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3′-untranslated region. Silencing LncRNA–NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox.ConclusionsThe results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA–NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.
Highlights
The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers
Echocardiography showed that left ventricular ejection fraction (EF) and fractional shortening (FS) significantly decreased, which was recovered by exosomesMIF, in the Dox group compared with the control group
ExosomeMIF prevented the cardiac injury process mediated by LncRNA–Nuclear paraspeckle assembly transcript 1 (NEAT1) transfer The microarray analysis between exosome and exosomeMIF was performed to determine whether exosomes could prevent the senescence process mediated by long noncoding RNAs (lncRNAs)
Summary
The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). Advances in cancer chemotherapy have led to a remarkable decrease in mortality rates and, a rapid increase in the number of cancer survivors [1]. Many of these cancer survivors suffer from chemotherapy-related cardiac complications later in life. Further exploration of the method alleviating Dox-induced cardiac senescence is warranted for the development of effective cardioprotective strategies
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