MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat.
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.
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Elena
E
Piegari
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Rosa
R
Russo
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Donato
D
Cappetta
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Grazia
G
Esposito
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Konrad
K
Urbanek
Institute of Genetics and Biophysics, IGB 'Adriano Buzzati-Traverso', Naples, Italy.
Carmela
C
Dell'Aversana
Institute of Genetics and Biophysics, IGB 'Adriano Buzzati-Traverso', Naples, Italy.|Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Lucia
L
Altucci
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Liberato
L
Berrino
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Francesco
F
Rossi
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
Antonella
A
De Angelis
D000107:Acetylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D009202:Cardiomyopathies / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D066126:Cardiotoxicity / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D042783:Endothelial Cells; D005260:Female; D006321:Heart / Q000187:drug effects*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C000617196:Bcl2 protein, rat; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
SIRT1; cellular senescence; doxorubicin-induced cardiotoxicity; miR-34a; rat cardiac progenitor cells
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