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© 2017 Ludke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

We previously reported that Vitamin C (Vit C) protects against doxorubicin (Dox)-induced cardiotoxicity by reducing oxidative stress, p38 mitogen-activated kinase (MAPK) and p53 activation and rescuing cell death in isolated adult cardiomyocytes. The pattern of activation and the role of oxidative stress as well as down-stream mechanisms for such protection remain elusive. Therefore the present study aims to analyze time-dependant generation of reactive oxygen species (ROS) and the activation of stress induced signalling pathways in cardiomyocytes treated with Dox and Vit C. The data provides further understanding of heart pathophysiology in response to Dox at the cellular level, and may help to optimize the timing of various therapeutic approaches. Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to Dox (10 μM), Vit C (25 μM), and Dox + Vit C for different time intervals up to 24 h. p38-JNK (SB203580) and p53 (pifithrin-α) inhibitors were used to determine the role of each respective signalling protein. Dox administration to cardiomyocytes increased the levels of ROS in a time-dependent manner that followed the activation of stress-induced proteins p53, p38 and JNK MAPKs, culminating in an increase in autophagy and apoptosis markers. Dox-induced increase in ROS was alleviated by Vit C adjuvant treatment at all time-points and this was also correlated with blunting of the activation of the studied signaling pathways leading to the prevention of apoptosis and preservation of cell viability. Protective effect of Vit C against the activation of stress induced proteins, autophagy and apoptosis was mainly attributed to its antioxidant properties even though blockage of p38, JNK and p53 by pharmacological inhibitors also suppressed Dox-induced apoptosis. ROS is defined as a key inducer of cardiomyocyte damage under Dox exposure; Vit C could effectively counteract all Dox-induced changes in cardiomyocytes and may potentially be used as an antioxidant adjuvant therapy to protect against Dox-induced cardiomyopathy.

Details

Title
Time course of changes in oxidative stress and stress-induced proteins in cardiomyocytes exposed to doxorubicin and prevention by vitamin C
Author
Ludke, Ana; Akolkar, Gauri; Ayyappan, Prathapan; Sharma, Anita K; Singal, Pawan K
First page
e0179452
Section
Research Article
Publication year
2017
Publication date
Jul 2017
Publisher
Public Library of Science
e-ISSN
19326203
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1916506750
Copyright
© 2017 Ludke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.