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Updated: Aug 7, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione
Ye Xiong1, Xuwan Liu, Chuan-Pu Lee
1Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Abstract:
The cardiac toxicity of doxorubicin (DOX), a potent anticancer anthracycline antibiotic, is believed to be mediated through the generation of reactive oxygen species (ROS) in cardiomyocytes. This study aims to determine the function of cellular glutathione peroxidase (Gpx1), which is located in both mitochondria and cytosol, in defense against DOX-induced cardiomyopathy using a line of transgenic mice with cardiac overexpression of Gpx1. The Gpx1-overexpressing hearts were markedly more resistant than nontransgenic hearts to DOX-induced acute functional derangements, including impaired contractility and diastolic properties, decreased coronary flow rate, and reduced heart rate. In addition, DOX treatment impairs mitochondrial function of nontransgenic hearts as evident in a decreased rate of NAD-linked State 3 respiration, presumably a result of inactivation of complex I activity. This is associated with increases in the rates of NAD- and FAD-linked State 4 respiration and declines in P/O ratio, suggesting that the electron transfer and oxidative phosphorylation are uncoupled in these mitochondrial samples. These functional deficits of mitochondria could be largely prevented by Gpx1 overexpression. Taken together, these studies provide new evidence to further support the role of ROS, particularly H(2)O(2) and/or fatty acid hydroperoxides, in causing contractile and mitochondrial dysfunction in mouse hearts acutely exposed to DOX.
Insights
Cellular glutathione peroxidase (Gpx1) protects against doxorubicin (DOX) cardiotoxicity by reducing reactive oxygen species (ROS). Gpx1 overexpression in mice hearts prevented DOX-induced cardiac and mitochondrial dysfunction.
Area of Science:
- Cardiology
- Biochemistry
- Toxicology
Background:
- Doxorubicin (DOX) is a potent anticancer drug with known cardiac toxicity.
- This toxicity is primarily attributed to the generation of reactive oxygen species (ROS) in cardiomyocytes.
- Cellular glutathione peroxidase (Gpx1) is a key antioxidant enzyme found in mitochondria and cytosol.
Purpose of the Study:
- To investigate the protective role of cellular glutathione peroxidase (Gpx1) against doxorubicin (DOX)-induced cardiotoxicity.
- To evaluate the efficacy of cardiac Gpx1 overexpression in preventing DOX-induced cardiomyopathy.
- To elucidate the mechanisms underlying DOX-induced cardiac and mitochondrial dysfunction.
Main Methods:
- Utilized a transgenic mouse model with cardiac-specific overexpression of Gpx1.
- Administered doxorubicin (DOX) to both Gpx1-overexpressing and nontransgenic mice.
- Assessed cardiac function, including contractility, diastolic properties, coronary flow rate, and heart rate.
- Evaluated mitochondrial respiration (State 3 and State 4) and oxidative phosphorylation efficiency (P/O ratio).
Main Results:
- Gpx1-overexpressing hearts exhibited significant resistance to DOX-induced acute functional impairments compared to nontransgenic hearts.
- DOX treatment led to impaired mitochondrial function in nontransgenic hearts, characterized by decreased NAD-linked State 3 respiration and uncoupled oxidative phosphorylation.
- Gpx1 overexpression largely prevented these DOX-induced mitochondrial deficits.
- ROS, including H(2)O(2) and fatty acid hydroperoxides, were implicated in DOX-induced contractile and mitochondrial dysfunction.
Conclusions:
- Gpx1 plays a critical protective role against doxorubicin (DOX)-induced cardiotoxicity.
- Overexpression of Gpx1 in the heart mitigates DOX-induced cardiac and mitochondrial dysfunction.
- These findings reinforce the role of ROS in mediating DOX cardiotoxicity and highlight Gpx1 as a potential therapeutic target.
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