Oncotarget

Research Papers:

MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat

Elena Piegari _, Rosa Russo, Donato Cappetta, Grazia Esposito, Konrad Urbanek, Carmela Dell’Aversana, Lucia Altucci, Liberato Berrino, Francesco Rossi and Antonella De Angelis

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Oncotarget. 2016; 7:62312-62326. https://doi.org/10.18632/oncotarget.11468

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Abstract

Elena Piegari1,*, Rosa Russo1,*, Donato Cappetta1, Grazia Esposito1, Konrad Urbanek1, Carmela Dell’Aversana2, Lucia Altucci2,3, Liberato Berrino1, Francesco Rossi1, Antonella De Angelis1

1Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy

2Institute of Genetics and Biophysics, IGB ‘Adriano Buzzati-Traverso’, Naples, Italy

3Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy

*These authors have contributed equally to this work

Correspondence to:

Elena Piegari, email: [email protected]

Keywords: miR-34a, doxorubicin-induced cardiotoxicity, rat cardiac progenitor cells, SIRT1, cellular senescence

Received: February 03, 2016    Accepted: July 26, 2016    Published: August 22, 2016

ABSTRACT

New strategies to prevent and early detect the cardiotoxic effects of the anticancer drug doxorubicin (DOXO) are required. MicroRNAs emerged as potential diagnostic, therapeutic and prognostic approaches in cardiovascular diseases. MiR-34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with DOXO cardiotoxicity. Our in vitro and in vivo results indicated that after DOXO exposure the levels of miR-34a are enhanced in cardiac cells, including Cardiac Progenitor Cells (CPCs). Since one of the determining event responsible for the initiation and evolution of the DOXO toxicity arises at the level of the CPC compartment, we evaluated if miR-34a pharmacological inhibition in these cells ameliorates the detrimental aftermath of the drug. AntimiR-34a has beneficial consequences on vitality, proliferation, apoptosis and senescence of DOXO-treated rat CPC. These effects are mediated by an increase of prosurvival miR-34a targets Bcl-2 and SIRT1, accompanied by a decrease of acetylated-p53 and p16INK4a. Importantly, miR-34a silencing also reduces the release of this miRNA from DOXO-exposed rCPCs, decreasing its negative paracrine effects on other rat cardiac cells. In conclusion, the silencing of miR-34a could represent a future therapeutic option for cardioprotection in DOXO toxicity and at the same time, it could be considered as a circulating biomarker for anthracycline-induced cardiac damage.


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