Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase.
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.
Xiong
Ye
Y
Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Liu
Xuwan
X
Lee
Chuan-Pu
CP
Chua
Balvin H L
BH
Ho
Ye-Shih
YS
D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D000094765:Glutathione Peroxidase GPX1
D004317:Doxorubicin; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D042967:Electron Transport Complex I; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse