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Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in ß-adrenergic signaling and enhances apoptosis
journal contribution
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 StebbingThe 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.
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Publication status
- Published
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- Published version
Journal
Cell Death & DiseaseISSN
2041-4889Publisher
Springer NatureExternal DOI
Volume
6Article number
e1754Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-06-15First Open Access (FOA) Date
2018-06-15First Compliant Deposit (FCD) Date
2018-06-15Usage metrics
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