Long-noncoding RNA MALAT1 sponges microRNA-92a-3p to inhibit doxorubicin-induced cardiac senescence by targeting ATG4a.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 (exosome Hypoxia ) display pro-metabolism and pro-survival abilities. Several long-noncoding RNAs/microRNAs act as competing endogenous RNAs (ceRNAs) modulating DIC. No study investigated whether exosome Hypoxia 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 exosome Hypoxia . TargetScan and luciferase assay showed that miR-92a-3p targeted the ATG4a 3' untranslated region. Silencing ATG4a blocked the anti-senescent effect of exosome Hypoxia .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 exosome Hypoxia in Dox-ind

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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