The Determining Role of Mitochondrial Reactive Oxygen Species Generation and Monoamine Oxidase Activity in Doxorubicin-Induced Cardiotoxicity.

Antioxidants & Redox Signaling
Salvatore AntonucciFabio Di Lisa

Abstract

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+] homeos...Continue Reading

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Citations

Feb 9, 2021·Cell Calcium·Salvatore AntonucciNina Kaludercic
May 1, 2021·Free Radical Biology & Medicine·Umberto AttanasioValentina Mercurio

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Methods Mentioned

BETA
deamination
transfection
MDA
transmission electron microscopy
confocal microscopy
Fluorescence
protein assay

Key Resources (RRID) Mentioned

Addgene_64977

Software Mentioned

ImageJ
Origin Pro
Fiji

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