title: Involvement of ferritin heavy chain in the preventive effect of metformin against doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin is a wide-spectrum chemotherapeutic agent, although a cumulative dose may cause cardiac damage and lead to heart failure. Doxorubicin cardiotoxicity is dependent on the intracellular iron pool and manifests itself by increasing oxidative stress. Our group has recently shown the ability of metformin, an oral antidiabetic with cardiovascular benefits, to protect cardiomyocytes from doxorubicin-induced damage. This work aimed to study whether metformin is able to modulate the expression of ferritin, the major intracellular iron storage protein, in cardiomyocytes and whether it is involved in their protection. The addition of metformin to adult mouse cardiomyocytes (HL-1 cell line) induced both gene and protein expression of the ferritin heavy chain (FHC) in a time-dependent manner. The silencing of FHC expression with siRNAs inhibited the ability of metformin to protect cardiomyocytes from doxorubicin-induced damage, in terms of the percentage of cell viability, the levels of reactive oxygen species, and the activity of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase). In addition, metformin induced the activation of NF-κB in HL-1 cells, whereas preincubation with SN50, an inhibitor of NF-κB, blocked the upregulation of the FHC and the protective effect mediated by metformin. Taken together, these results provide new knowledge on the protective actions of metformin against doxorubicin-induced cardiotoxicity by identifying FHC and NF-κB as the major mediators of this beneficial effect.
authors.affiliation: Cardiology Department, University Hospital Virgen de Arrixaca, and Department of Medicine, School of Medicine, University of Murcia, 30120 Murcia, Spain.
authors.forename: Mari C
authors.initials: MC
authors.lastname: Asensio-López
authors.forename: Jesús
authors.initials: J
authors.lastname: Sánchez-Más
authors.forename: Domingo A
authors.initials: DA
authors.lastname: Pascual-Figal
authors.forename: Sergio
authors.initials: S
authors.lastname: Abenza
authors.forename: María T
authors.initials: MT
authors.lastname: Pérez-Martínez
authors.forename: Mariano
authors.initials: M
authors.lastname: Valdés
authors.forename: Antonio
authors.initials: A
authors.lastname: Lax
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism*; D054715:Cardiotoxins; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D010455:Peptides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C118258:SN50 peptide; D004317:Doxorubicin; D001052:Apoferritins; D008687:Metformin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase