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Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in ß-adrenergic signaling and enhances apoptosis

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posted on 2023-06-09, 13:47 authored by L Roca-Alonso, Leandro CastellanoLeandro Castellano, A Mills, A F Dabrowska, M B Sikkel, L Pellegrino, J Jacob, A E Frampton, J Krell, R C Coombes, S E Harding, A R Lyon, J Stebbing
The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the ß-adrenergic pathway, where preferential ß1- and ß2-adrenoceptor (ß1AR and ß2AR) direct inhibition is combined with Gia-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines.

History

Publication status

  • Published

File Version

  • Published version

Journal

Cell Death & Disease

ISSN

2041-4889

Publisher

Springer Nature

Volume

6

Article number

e1754

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-06-15

First Open Access (FOA) Date

2018-06-15

First Compliant Deposit (FCD) Date

2018-06-15

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