Han Tang1, Aibin Tao2, Jia Song1, Qian Liu1, Hao Wang1, Tao Rui3. 1. Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China. 2. Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China; Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada. 3. Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China; Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Critical Care Western, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Departments of Medicine, Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: trui@uwo.ca.
Abstract
BACKGROUND: Doxorubicin (DOX) is an anti-tumor agent that is widely used in clinical setting for cancer treatment. The application of the DOX, however, is limited by its cardiac toxicity which can induce heart failure through an undefined mechanism. Mitofusin 2 (Mfn2) is a mitochondrial GTPase fusion protein that is located on the outer membrane of mitochondria (OMM). The Mfn2 plays an important role in mitochondrial fusion and fission. The aim of this study is to identify the role of the Mfn2 in DOX-induced cardiomyocyte apoptosis. METHODS: Cultured neonatal rat cardiomyocytes were used in this study. Mfn2 expression in cardiomyocytes was determined after the cardiomyocytes were challenged with DOX. Cardiomyocyte mitochondrial fission, mitochondrial reactive oxygen species (ROS) production was assessed with mitochondrial fragmentation and MitoSOX fluorescence probe, respectively. Cardiomyocyte apoptosis was determined with caspase3 activity and TUNEL staining. RESULTS: Challenging of the cardiomyocytes with DOX resulted in increasing in cardiomyocyte oxidative stress and apoptosis. In addition, levels of Mfn2 in cardiomyocytes were decreased after the cells were challenged with DOX which was associated with increased mitochondrial fission (fragmentation) and mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 attenuated the DOX-induced increase in mitochondrial fission and prevented cardiomyocyte mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 or pretreatment of cardiomyocytes with an anti-oxidant, Mito-tempo, also prevented the DOX-induced cardiomyocyte apoptosis. CONCLUSION: Our results indicate that DOX results in a decreased cardiomyocyte Mfn2 expression which promotes mitochondrial fission and ROS production further leads to cardiomyocyte apoptosis.
BACKGROUND:Doxorubicin (DOX) is an anti-tumor agent that is widely used in clinical setting for cancer treatment. The application of the DOX, however, is limited by its cardiac toxicity which can induce heart failure through an undefined mechanism. Mitofusin 2 (Mfn2) is a mitochondrial GTPase fusion protein that is located on the outer membrane of mitochondria (OMM). The Mfn2 plays an important role in mitochondrial fusion and fission. The aim of this study is to identify the role of the Mfn2 in DOX-induced cardiomyocyte apoptosis. METHODS: Cultured neonatal rat cardiomyocytes were used in this study. Mfn2 expression in cardiomyocytes was determined after the cardiomyocytes were challenged with DOX. Cardiomyocyte mitochondrial fission, mitochondrial reactive oxygen species (ROS) production was assessed with mitochondrial fragmentation and MitoSOX fluorescence probe, respectively. Cardiomyocyte apoptosis was determined with caspase3 activity and TUNEL staining. RESULTS: Challenging of the cardiomyocytes with DOX resulted in increasing in cardiomyocyte oxidative stress and apoptosis. In addition, levels of Mfn2 in cardiomyocytes were decreased after the cells were challenged with DOX which was associated with increased mitochondrial fission (fragmentation) and mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 attenuated the DOX-induced increase in mitochondrial fission and prevented cardiomyocyte mitochondrial ROS production. An increase in cardiomyocyte levels of Mfn2 or pretreatment of cardiomyocytes with an anti-oxidant, Mito-tempo, also prevented the DOX-induced cardiomyocyte apoptosis. CONCLUSION: Our results indicate that DOX results in a decreased cardiomyocyte Mfn2 expression which promotes mitochondrial fission and ROS production further leads to cardiomyocyte apoptosis.
Authors: Xiaoxue Yu; Yang Ruan; Tao Shen; Quan Qiu; Mingjing Yan; Shenghui Sun; Lin Dou; Xiuqing Huang; Que Wang; Xiyue Zhang; Yong Man; Weiqing Tang; Zening Jin; Jian Li Journal: Biomed Res Int Date: 2020-03-01 Impact factor: 3.411