Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes

Asensio Lopez, Maria del Carmen; Pascual Figal, Domingo A.; Fernandez Belda, Franscisco; Lax Pérez, Antonio Manuel; Soler Pardo, Fernando

Publication:
Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes

dc.contributor.author	Asensio Lopez, Maria del Carmen
dc.contributor.author	Pascual Figal, Domingo A.
dc.contributor.author	Fernandez Belda, Franscisco
dc.contributor.author	Lax Pérez, Antonio Manuel
dc.contributor.author	Soler Pardo, Fernando
dc.contributor.department	Medicina
dc.date.accessioned	2024-01-22T11:54:26Z
dc.date.available	2024-01-22T11:54:26Z
dc.date.issued	2017-02
dc.description	©2017. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by /4.0/ This document is the Published version of a Published Work that appeared in final form in PLoS ONE. To access the final edited and published work see https://doi.org/10.1371/journal.pone.0172803	es
dc.description.abstract	The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced by caffeine and the increase in lipid peroxidation, both of which are indicators of doxorubicin-induced oxidative stress, were also prevented by nicorandil.	es
dc.format	application/pdf	es
dc.format.extent	21	es
dc.identifier.citation	PLoS ONE
dc.identifier.doi	10.1371/journal.pone.0172803
dc.identifier.issn	1932-6203
dc.identifier.uri	http://hdl.handle.net/10201/137513
dc.language	eng	es
dc.relation	This study was supported by Grants FFIS/CM10/011 from Fundacio´n CajaMurcia, Murcia, Spain to AL and PI14/01637 from Spanish Instituto de Salud Carlos III to DPF. Dr. Antonio Lax was supported by a Sara Borrell employment contract (CD13/00032) from the Spanish Instituto de Salud Carlos III.	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	*
dc.title	Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es
relation.isAuthorOfPublication	fb419085-b327-4302-860b-d0f7e5000ea9
relation.isAuthorOfPublication.latestForDiscovery	fb419085-b327-4302-860b-d0f7e5000ea9