title: Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in β-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 β-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-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.
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: L
authors.initials: L
authors.lastname: Roca-Alonso
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: L
authors.identifier: 0000000230594829
authors.initials: L
authors.lastname: Castellano
authors.affiliation: National Heart and Lung Institute, Imperial College, 4th Floor, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mills
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Dabrowska
authors.affiliation: National Heart and Lung Institute, Imperial College, 4th Floor, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: M B
authors.initials: MB
authors.lastname: Sikkel
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: L
authors.initials: L
authors.lastname: Pellegrino
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Jacob
authors.affiliation: 1] Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [2] Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Krell
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: National Heart and Lung Institute, Imperial College, 4th Floor, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Harding
authors.affiliation: 1] National Heart and Lung Institute, Imperial College, 4th Floor, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [2] NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Imperial college, London SW3 6NP, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, 1st Floor, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D050993:GATA6 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C084364:Gata6 protein, rat; C556157:MIRN30 microRNA, rat; D035683:MicroRNAs; D011943:Receptors, Adrenergic, beta; D004317:Doxorubicin