Attenuation of Doxorubicin-Induced Cardiac Injury by Mitochondrial Glutaredoxin 2

Authors

Nicole M. Diotte, Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, 2727 Second Avenue, Room 4000, Detroit, MI
Ye Xiong, Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, 2727 Second Avenue, Room 4000, Detroit, MI
Jinping Gao, East Tennessee State University; and James H. Quillen Veterans Affairs Medical Center, Johnson City, TN, USA
Balvin H.L. Chua, East Tennessee State University; and James H. Quillen Veterans Affairs Medical Center, Johnson City, TN, USA
Ye-Shih Ho, Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, 2727 Second Avenue, Room 4000, Detroit, MI

Date of this Version

2009

Comments

Published in Biochimica et Biophysica Acta 1793 (2009) 427–438. This is a US government work, not subject to copyright in the United States.

Abstract

While the cardiotoxicity of doxorubicin (DOX) is known to be partly mediated through the generation of reactive oxygen species (ROS), the biochemical mechanisms by which ROS damage cardiomyocytes remain to be determined. This study investigates whether S-glutathionylation of mitochondrial proteins plays a role in DOX-induced myocardial injury using a line of transgenic mice expressing the human mitochondrial glutaredoxin 2 (Glrx2), a thiotransferase catalyzing the reduction as well as formation of protein–glutathione mixed disulfides, in cardiomyocytes. The total glutaredoxin (Glrx) activity was increased by 76% and 53 fold in homogenates of whole heart and isolated heart mitochondria of Glrx2 transgenic mice, respectively, compared to those of nontransgenic mice. The expression of other antioxidant enzymes, with the exception of glutaredoxin 1, was unaltered. Overexpression of Glrx2 completely prevents DOX-induced decreases in NAD- and FAD-linked state 3 respiration and respiratory control ratio (RCR) in heart mitochondria at days 1 and 5 of treatment. The extent of DOX-induced decline in left ventricular function and release of creatine kinase into circulation at day 5 of treatment was also greatly attenuated in Glrx2 transgenic mice. Further studies revealed that heart mitochondria overexpressing Glrx2 released less cytochrome c than did controls in response to treatment with tBid or a peptide encompassing the BH3 domain of Bid. Development of tolerance to DOX toxicity in transgenic mice is also associated with an increase in protein S-glutathionylation in heart mitochondria. Taken together, these results imply that S-glutathionylation of heart mitochondrial proteins plays a role in preventing DOX-induced cardiac injury.