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

Ryan N Montalvo; Vivian Doerr; Oh Sung Kwon; Erin E Talbert; Jeung-Ki Yoo; Moon-Hyon Hwang; Branden L Nguyen; Demetra D Christou; Andreas N Kavazis; Ashley J Smuder

doi:10.3390/ijms21218105

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

Journal article

Open access

Peer reviewed

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

Ryan N Montalvo, Vivian Doerr, Oh Sung Kwon, Erin E Talbert, Jeung-Ki Yoo, Moon-Hyon Hwang, Branden L Nguyen, Demetra D Christou, Andreas N Kavazis and Ashley J Smuder

International journal of molecular sciences, Vol.21(21), pp.1-12

10/30/2020

DOI: 10.3390/ijms21218105

PMCID: PMC7662380

PMID: 33143122

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Abstract

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.

Animals

Antibiotics, Antineoplastic - toxicity

Autophagy

Autophagy-Related Protein 5 - genetics

Autophagy-Related Protein 5 - metabolism

Cardiotoxicity - etiology

Cardiotoxicity - pathology

Cardiotoxicity - prevention & control

Doxorubicin - toxicity

Male

Membrane Potential, Mitochondrial

Oxidative Stress - drug effects

Rats

Rats, Sprague-Dawley

Reactive Oxygen Species - metabolism

Signal Transduction

Details

Title: Subtitle: Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
Creators: Ryan N Montalvo - University of Florida
Vivian Doerr - University of Florida
Oh Sung Kwon - University of Connecticut
Erin E Talbert - University of Iowa
Jeung-Ki Yoo - University of Florida
Moon-Hyon Hwang - University of Florida
Branden L Nguyen - University of Florida
Demetra D Christou - University of Florida
Andreas N Kavazis - University of Michigan
Ashley J Smuder - University of Florida
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.21(21), pp.1-12
DOI: 10.3390/ijms21218105
PMID: 33143122
PMCID: PMC7662380
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Grant note: 17GRNT33661052 / American Heart Association 17GRNT33661052 / American Heart Association-American Stroke Association R01 HL144858 / NHLBI NIH HHS P30 CA086862 / NCI NIH HHS R01HL144858 / NHLBI NIH HHS
Language: English
Date published: 10/30/2020
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984259652202771

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