Abstract
The clinical application of doxorubicin (Dox) is limited due to its undesirable cardiotoxicity side effects. Cellular senescence plays an important role in Dox-induced cardiotoxicity. Exosomes derived from stem cells showed a therapeutic effect in Dox-induced cardiomyopathy (DIC). Hypoxia-preconditioned exosomes (exosomeHypoxia) display pro-metabolism and pro-survival abilities. Several long-noncoding RNAs/microRNAs act as competing endogenous RNAs (ceRNAs) modulating DIC. No study investigated whether exosomeHypoxia could attenuate DIC through modulating ceRNAs.Treatment of the human adipose–derived mesenchymal stem cells with hypoxia induced lncRNA-MALAT1 accumulation in the secreted exosomes. In addition, the lncRNA-MALAT1 was identified as an exosomal transfer RNA to repress miR-92a-3p expression. Silencing the lncRNA-MALAT1 in MSCs or miR-92a-3p overexpression in cardiomyocytes significantly impaired the rejuvenation induced by exosomeHypoxia. TargetScan and luciferase assay showed that miR-92a-3p targeted the ATG4a 3' untranslated region. Silencing ATG4a blocked the anti-senescent effect of exosomeHypoxia.This study identified the lncRNA-MALAT1 that functioned as ceRNA binding to miR-92a-3p, leading to ATG4a activation, thus improving mitochondrial metabolism. LncRNA-MALAT1/miR-92a-3p/ATG4a partially mediates the cardioprotective roles of exosomeHypoxia in Dox-induced cardiac damage. ExosomeHypoxia may serve as a potential therapeutic target against DIC.
Highlights
With the improvement in cancer-related outcomes, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors
The present study aimed to investigate the role of the Long-noncoding RNAs (lncRNAs)-Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) transferred by exosomesHypoxia derived from Mesenchymal stem cells (MSCs) in resisting Dox-induced cardiac senescence
Exosomes derived from MSCs pretreated with hypoxia had a better cardioprotective effect Considering the promoting effect of hypoxia preconditioning, the present study evaluated whether exosomes secreted by MSCs pretreated with hypoxia showed a more cardioprotective effect
Summary
With the improvement in cancer-related outcomes, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Most cardiotoxic agents include anthracyclines, such as Dox [1]. A retrospective analysis of the clinical use of Dox in adults showed that the incidence of congestive heart failure increased from 3% to 5% at a dose of 400 mg - m−2 and from. Cardiac toxicity caused by Dox has serious consequences, resulting in a poor prognosis and death for up to 61% of patients [2, 3]. It is generally believed that Dox-induced cardiac toxicity mainly involves metabolism disruption, leading to cellular senescence [4, 5]. Based on the aforementioned mechanism, studies on Dox-induced senescence have attracted wide attention in recent years
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