The Determining Role of Mitochondrial Reactive Oxygen Species Generation and Monoamine Oxidase Activity in Doxorubicin-Induced Cardiotoxicity
Autor: | Alberto Bindoli, Moises Di Sante, Fabio Di Lisa, Maria Pia Rigobello, Marco Giorgio, Roberta Menabò, Laura Pontarollo, Andrea Carpi, Federica Tonolo, Nina Kaludercic, Petra Alanova, Salvatore Antonucci, Valeria Scalcon |
---|---|
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Programmed cell death Physiology Monoamine oxidase Heart Ventricles Clinical Biochemistry Cardiomyopathy Mitochondrion Pharmacology reactive oxygen species (ROS) medicine.disease_cause Biochemistry 03 medical and health sciences Mice medicine Animals Doxorubicin Myocytes Cardiac Molecular Biology Monoamine Oxidase General Environmental Science Cardiotoxicity Forum Original Research Communications 030102 biochemistry & molecular biology Chemistry Cell Biology medicine.disease Mitochondria Rats Oxidative Stress cardiomyopathy doxorubicin mitochondria monoamine oxidase 030104 developmental biology Reactive oxygen species generation General Earth and Planetary Sciences Reactive Oxygen Species Oxidative stress medicine.drug |
Zdroj: | Antioxid Redox Signal |
ISSN: | 1557-7716 |
Popis: | 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 H(2)O(2) 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 [Ca(2+)] 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. |
Databáze: | OpenAIRE |
Externí odkaz: |