Ferritin heavy chain as main mediator of preventive effect of metformin against mitochondrial damage induced by doxorubicin in cardiomyocytes

Asensio Lopez, Maria del Carmen; Sanchez Mas, Jesus; Pascual Figal, Domingo A.; de la Torre, Carlos; Valdes, Mariano; Lax Pérez, Antonio Manuel

Publication:
Ferritin heavy chain as main mediator of preventive effect of metformin against mitochondrial damage induced by doxorubicin in cardiomyocytes

dc.contributor.author	Asensio Lopez, Maria del Carmen
dc.contributor.author	Sanchez Mas, Jesus
dc.contributor.author	Pascual Figal, Domingo A.
dc.contributor.author	de la Torre, Carlos
dc.contributor.author	Valdes, Mariano
dc.contributor.author	Lax Pérez, Antonio Manuel
dc.contributor.department	Medicina
dc.date.accessioned	2024-01-23T12:25:01Z
dc.date.available	2024-01-23T12:25:01Z
dc.date.issued	2014-02
dc.description	©2014. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted version of a Published Work that appeared in final form inFree Radical Biology and Medicine. To access the final edited and published work see https://doi.org/10.1016/j.freeradbiomed.2013.11.003	es
dc.description.abstract	The efficacy of doxorubicin (DOX) as an antitumor agent is greatly limited by the induction of cardiomyopathy, which results from mitochondrial dysfunction and iron-catalyzed oxidative stress in the cardiomyocyte. Metformin (MET) has been seen to have a protective effect against the oxidative stress induced by DOX in cardiomyocytes through its modulation of ferritin heavy chain (FHC), the main iron-storage protein. This study aimed to assess the involvement of FHC as a pivotal molecule in the mitochondrial protection offered by MET against DOX cardiotoxicity. The addition of DOX to adult mouse cardiomyocytes (HL-1 cell line) increased the cytosolic and mitochondrial free iron pools in a time-dependent manner. Simultaneously, DOX inhibited complex I activity and ATP generation and induced the loss of mitochondrial membrane potential. The mitochondrial dysfunction induced by DOX was associated with the release of cytochrome c to the cytosol, the activation of caspase 3, and DNA fragmentation. The loss of iron homeostasis, mitochondrial dysfunction, and apoptosis induced by DOX were prevented by treatment with MET 24h before the addition of DOX. The involvement of FHC and NF-κB was determined through siRNA-mediated knockdown. Interestingly, the presilencing of FHC or NF-κB with specific siRNAs blocked the protective effect induced by MET against DOX cardiotoxicity. These findings were confirmed in isolated primary neonatal rat cardiomyocytes. In conclusion, these results deepen our knowledge of the protective action of MET against DOX-induced cardiotoxicity and suggest that therapeutic strategies based on FHC modulation could protect cardiomyocytes from the mitochondrial damage induced by DOX by restoring iron homeostasis	es
dc.format	application/pdf	es
dc.format.extent	11	es
dc.identifier.citation	Free Radic Biol Med. 2014 Feb:67:19-29.doi: 10.1016/j.freeradbiomed.2013.11.003. Epub 2013 Nov 11.
dc.identifier.doi	10.1016/j.freeradbiomed.2013.11.003
dc.identifier.issn	1873-4596
dc.identifier.issn	0891-5849
dc.identifier.uri	http://hdl.handle.net/10201/137593
dc.language	eng	es
dc.relation	This study was supported in part by Grant 11857/PI/09 (to D.A.P.-F.) from the Fundación Séneca, Murcia, Spain; by Grant PS09/02106 (to M.V.) from the Ministerio de Sanidad, Madrid, Spain; and by the National Network of Investigation in Cardiovascular Diseases (RD12/0042/0049).	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights	Attribution-NonCommercial-NoDerivatives 4.0 Internacional	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	*
dc.subject	Cardiotoxicity	es
dc.subject	Doxorubicin	es
dc.subject	Metformin	es
dc.subject	Ferritin	es
dc.subject	Iron homeostasis	es
dc.subject	Mitochondrial function	es
dc.subject	Free radicals	es
dc.title	Ferritin heavy chain as main mediator of preventive effect of metformin against mitochondrial damage induced by doxorubicin in cardiomyocytes	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es