Publication: Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes
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Date
2016
Authors
Asensio Lopez, Maria del Carmen ; Sanchez Mas, Jesus ; Pascual Figal, Domingo A. ; Fernandez Belda, Francisco ; Lax Pérez, Antonio Manuel ; Soler Pardo, Fernando
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Publisher
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DOI
10.1016/j.abb.2016.02.021
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info:eu-repo/semantics/article
Description
©2016. 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 in Archives of Biochemistry and Biophysics. To access the final edited and published work see https://doi.org/10.1016/j.abb.2016.02.021
Abstract
In atrial-derived HL-1 cells, ryanodine receptor and Naþ/Ca2þ-exchanger were altered early by 5 mM
doxorubicin. The observed effects were an increase of cytosolic Ca2þ at rest, ensuing ryanodine receptor
phosphorylation, and the slowing of Ca2þ transient decay after caffeine addition. Doxorubicin triggered a
linear rise of reactive oxygen species (ROS) with no early effect on mitochondrial inner membrane potential. Doxorubicin and ROS were both detected in mitochondria by colocalization with fluorescence
probes and doxorubicin-induced ROS was totally blocked by mitoTEMPO. The NADPH oxidase activity in
the mitochondrial fraction was sensitive to inhibition by GKT137831, and doxorubicin-induced ROS
decreased gradually as the GKT137831 concentration added in preincubation was increased. When
doxorubicin-induced ROS was prevented by GKT137831, the kinetic response revealed a permanent
degree of protection that was consistent with mitochondrial NADPH oxidase inhibition. In contrast, the
ROS induction by doxorubicin after melatonin preincubation was totally eliminated at first but the effect
was completely reversed with time. Limiting the source of ROS production is a better alternative for
dealing with oxidative damage than using ROS scavengers. The short-term effect of doxorubicin on Ca2þ
transporters involved in myocardiac contractility was dependent on oxidative damage, and so the
impairment was subsequent to ROS production.
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Citation
Arch Biochem Biophys. 2016 Mar 15:594:26-36.doi: 10.1016/j.abb.2016.02.021. Epub 2016 Feb 22.
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Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by-nc-nd/4.0/