RGD Reference Report - Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis. - Rat Genome Database

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

Authors: Roca-Alonso, L  Castellano, L  Mills, A  Dabrowska, AF  Sikkel, MB  Pellegrino, L  Jacob, J  Frampton, AE  Krell, J  Coombes, RC  Harding, SE  Lyon, AR  Stebbing, J 
Citation: Roca-Alonso L, etal., Cell Death Dis. 2015 May 7;6:e1754. doi: 10.1038/cddis.2015.89.
RGD ID: 11541106
Pubmed: PMID:25950484   (View Abstract at PubMed)
PMCID: PMC4669718   (View Article at PubMed Central)
DOI: DOI:10.1038/cddis.2015.89   (Journal Full-text)

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 beta-adrenergic pathway, where preferential beta1- and beta2-adrenoceptor (beta1AR and beta2AR) direct inhibition is combined with Gialpha-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
congestive heart failure  ISOMir30e (Rattus norvegicus)11541106; 11541106miRNA:decreased expression:heart (rat)RGD 
congestive heart failure  IEP 11541106miRNA:decreased expression:heart (rat)RGD 
myocardial infarction  ISOMir30e (Rattus norvegicus)11541106; 11541106miRNA:decreased expression:heart (rat)RGD 
myocardial infarction  IEP 11541106miRNA:decreased expression:heart (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
doxorubicin decreases expression ISOMir30e (Rattus norvegicus)11541106; 11541106Doxorubicin decreases expression of Mir30e miRNA in adult ventricular cardiomyocytesRGD 
doxorubicin decreases expression EXP 11541106Doxorubicin decreases expression of Mir30e miRNA in adult ventricular cardiomyocytesRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Gata6  (GATA binding protein 6)
Mir30e  (microRNA 30e)

Genes (Mus musculus)
Mir30e  (microRNA 30e)

Genes (Homo sapiens)
MIR30E  (microRNA 30e)


Additional Information