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

ABSTRACT: 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 ?-adrenergic pathway, where preferential ?1- and ?2-adrenoceptor (?1AR and ?2AR) direct inhibition is combined with Gi?-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.

SUBMITTER: Roca-Alonso L

PROVIDER: S-EPMC4669718 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Roca-Alonso L L Castellano L L Mills A A Dabrowska A F AF Sikkel M B MB Pellegrino L L Jacob J J Frampton A E AE Krell J J Coombes R C RC Harding S E SE Lyon A R AR Stebbing J J

Cell death & disease 20150507

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 bo ...[more]

PMID: 25950484

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Project description:Transforming growth factors beta (TGF-?) are multi-functional cytokines capable of inducing apoptosis in epithelial cells, including glomerular podocytes. We and others have previously shown that podocyte-selective genetic deletion of the microRNA (miR)-processing enzyme, Dicer, caused glomerulosclerosis that was associated with podocyte apoptosis, and the miR-30 family was implicated in the process. Here, we report that apoptosis-associated genes were highly enriched among the predicted targets of miR-30 when compared with randomly selected miRs (26% vs. 4.5 ± 2.1%) or with the known TGF-?-regulated miR-192 (6%), miR-216a (5.1%), and miR-217 (0%). miR-30 family members were abundantly expressed in podocytes in normal mice but were downregulated in albumin/TGF-? transgenic mice with podocyte apoptosis and glomerulosclerosis. In vitro, TGF-? downregulated miR-30s in wildtype and Smad3-deficient, but not Smad2- or Smad2/Smad3-deficient, podocytes. The TGF-?-induced activation of caspase 3 and an increase in TUNEL-positive nuclei were significantly inhibited by the lentivirus-mediated overexpression of miR-30d, but not by a scrambled control miR, in podocytes. TGF-? stimulated the phosphorylation of pro-apoptotic p53 in podocytes with lentiviral expression of a scrambled miR, but not in podocytes expressing miR-30d. In contrast, miR-30d had no effect on the phosphorylation of pro-apoptotic p38 MAP kinase induced by TGF-?. Thus, we report that Smad2-dependent inhibition of miR-30s in podocytes is required for the activation of p53 and the induction of apoptosis by TGF-?. These results demonstrate a novel functional role for miR-30 in podocyte survival and indicate that the loss of miR-30 survival signaling is a novel and specific mechanism of TGF-?-induced podocyte apoptosis during glomerulosclerosis. We propose the therapeutic replacement of miR-30 as a novel strategy to prevent the podocyte apoptosis that is characteristic of progressive glomerular diseases.

Dataset Information

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

Publications

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

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