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

Wenzheng Xia | Zendy; Hanbin Chen | Zendy; Congying Xie | Zendy; Meng Hou | Zendy

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

Author(s) -

Wenzheng Xia,

Hanbin Chen,

Congying Xie,

Meng Hou

Publication year - 2020

Publication title -

aging

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.473

H-Index - 90

ISSN - 1945-4589

DOI - 10.18632/aging.103136

Subject(s) - competing endogenous rna , malat1 , exosome , microrna , gene silencing , microvesicles , microbiology and biotechnology , biology , long non coding rna , cardiotoxicity , cancer research , rna , biochemistry , gene , genetics , chemotherapy

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-induced cardiac damage. Exosome Hypoxia may serve as a potential therapeutic target against DIC.

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