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The Determining Role of Mitochondrial Reactive Oxygen Species Generation and Monoamine Oxidase Activity in Doxorubicin-Induced Cardiotoxicity
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SYSNO ASEP 0541609 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název The Determining Role of Mitochondrial Reactive Oxygen Species Generation and Monoamine Oxidase Activity in Doxorubicin-Induced Cardiotoxicity Tvůrce(i) Antonucci, S. (IT)
Di Sante, M. (IT)
Tonolo, F. (IT)
Pontarollo, L. (IT)
Scalcon, V. (IT)
Alánová, Petra (FGU-C) RID, ORCID
Menabo, R. (IT)
Carpi, A. (IT)
Bindoli, A. (IT)
Rigobello, M. P. (IT)
Giorgio, M. (IT)
Kaludercic, N. (IT)
Di Lisa, F. (IT)Zdroj.dok. Antioxidants & Redox Signaling. - : Mary Ann Liebert - ISSN 1523-0864
Roč. 34, č. 7 (2021), s. 531-550Poč.str. 20 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova doxorubicin ; cardiomyopathy ; mitochondria ; monoamine oxidase ; reactive oxygen species (ROS) Vědní obor RIV ED - Fyziologie Obor OECD Physiology (including cytology) Způsob publikování Omezený přístup Institucionální podpora FGU-C - RVO:67985823 UT WOS 000547813800001 EID SCOPUS 85100745267 DOI 10.1089/ars.2019.7929 Anotace Aims: Doxorubicin cardiomyopathy is a lethal pathology characterized by oxidative stress, mitochondrial dysfunction, and contractile impairment, leading to cell death. Although extensive research has been done to understand the pathophysiology of doxorubicin cardiomyopathy, no effective treatments are available. We investigated whether monoamine oxidases (MAOs) could be involved in doxorubicin-derived oxidative stress, and in the consequent mitochondrial, cardiomyocyte, and cardiac dysfunction. Results: We used neonatal rat ventricular myocytes (NRVMs) and adult mouse ventricular myocytes (AMVMs). Doxorubicin alone (i.e., 0.5 μM doxorubicin) or in combination with H2O2 induced an increase in mitochondrial formation of reactive oxygen species (ROS), which was prevented by the pharmacological inhibition of MAOs in both NRVMs and AMVMs. The pharmacological approach was supported by the genetic ablation of MAO-A in NRVMs. In addition, doxorubicin-derived ROS caused lipid peroxidation and alterations in mitochondrial function (i.e., mitochondrial membrane potential, permeability transition, redox potential), mitochondrial morphology (i.e., mitochondrial distribution and perimeter), sarcomere organization, intracellular [Ca2+] homeostasis, and eventually cell death. All these dysfunctions were abolished by MAO inhibition. Of note, in vivo MAO inhibition prevented chamber dilation and cardiac dysfunction in doxorubicin-treated mice.
Innovation and Conclusion: This study demonstrates that the severe oxidative stress induced by doxorubicin requires the involvement of MAOs, which modulate mitochondrial ROS generation. MAO inhibition provides evidence that mitochondrial ROS formation is causally linked to all disorders caused by doxorubicin in vitro and in vivo. Based upon these results, MAO inhibition represents a novel therapeutic approach for doxorubicin cardiomyopathy.
Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2022 Elektronická adresa https://doi.org/10.1089/ars.2019.7929
Počet záznamů: 1