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Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardio...

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Autores principales: Montalvo, Ryan N., Doerr, Vivian, Kwon, Oh Sung, Talbert, Erin E., Yoo, Jeung-Ki, Hwang, Moon-Hyon, Nguyen, Branden L., Christou, Demetra D., Kavazis, Andreas N., Smuder, Ashley J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662380/
https://www.ncbi.nlm.nih.gov/pubmed/33143122
http://dx.doi.org/10.3390/ijms21218105
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author Montalvo, Ryan N.
Doerr, Vivian
Kwon, Oh Sung
Talbert, Erin E.
Yoo, Jeung-Ki
Hwang, Moon-Hyon
Nguyen, Branden L.
Christou, Demetra D.
Kavazis, Andreas N.
Smuder, Ashley J.
author_facet Montalvo, Ryan N.
Doerr, Vivian
Kwon, Oh Sung
Talbert, Erin E.
Yoo, Jeung-Ki
Hwang, Moon-Hyon
Nguyen, Branden L.
Christou, Demetra D.
Kavazis, Andreas N.
Smuder, Ashley J.
author_sort Montalvo, Ryan N.
collection PubMed
description Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.
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spelling pubmed-76623802020-11-14 Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition Montalvo, Ryan N. Doerr, Vivian Kwon, Oh Sung Talbert, Erin E. Yoo, Jeung-Ki Hwang, Moon-Hyon Nguyen, Branden L. Christou, Demetra D. Kavazis, Andreas N. Smuder, Ashley J. Int J Mol Sci Article Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences. MDPI 2020-10-30 /pmc/articles/PMC7662380/ /pubmed/33143122 http://dx.doi.org/10.3390/ijms21218105 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Montalvo, Ryan N.
Doerr, Vivian
Kwon, Oh Sung
Talbert, Erin E.
Yoo, Jeung-Ki
Hwang, Moon-Hyon
Nguyen, Branden L.
Christou, Demetra D.
Kavazis, Andreas N.
Smuder, Ashley J.
Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title_full Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title_fullStr Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title_full_unstemmed Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title_short Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
title_sort protection against doxorubicin-induced cardiac dysfunction is not maintained following prolonged autophagy inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662380/
https://www.ncbi.nlm.nih.gov/pubmed/33143122
http://dx.doi.org/10.3390/ijms21218105
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