Cited by 78Chemotherapy-induced cardiotoxicity and mitigationRedox biology and oxidative stressCardiac Ischemia and Reperfusion

Attenuation of doxorubicin-induced cardiac injury by mitochondrial glutaredoxin 2

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Diotte, Nicole M., Xiong, Ye, Gao, Jinping, Chua, Balvin H.L., Ho, Ye-Shih·2009·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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.

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Crossref · 10.1016/j.bbamcr.2008.10.014

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  • Upregulation of the Grx/GSH/GR system is protective against mitochondrial dysfunction and apoptosis by augmenting signaling cascades and/or preserving mitochondrial function.

    “In contrast, upregulation of the Grx/GSH/GR system is protective against mitochondrial dysfunction and apoptosis by augmenting signaling cascades and/or preserving mitochondrial function (119, 441).”

    From Redox regulation of mitochondrial function (2012) · cites this paper as [119]

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Authors
Diotte, N. M., Xiong, Y., Gao, J., Chua, B. H. L., & Ho, Y.-S.
Affiliations
  • Wayne State University (US)
  • East Tennessee State University (US)
Corresponding author
Ho, Ye-Shih
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2009-02
Volume
1793
Issue
2
Pages
427-438
ISSN
0167-4889 (ISSN-L)
OpenAlex
W2130130572
Cited by
78
References
70
Citations by year
2026: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 8 · 2012: 3
FWCI
4.61
Type
journal article
Language
en
Open access
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
  • Lincoln (University of Nebraska) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • American Heart Association
  • Wayne State University
  • University of Cincinnati
  • National Institutes of Health (ES06639, P30 ES06639)
  • National Heart, Lung, and Blood Institute (R15HL087271)
  • National Institute of Environmental Health Sciences (P-30-ES06639, ES06639)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
doxorubicin cardiotoxicity, S-glutathionylation, reactive oxygen species, cardiomyocytes, heart mitochondria, mitochondrial respiration, respiratory control ratio, cytochrome c release, transgenic mice, creatine kinase release, left ventricular function
MeSH terms
Animals, Creatine Kinase, Doxorubicin, Flavin-Adenine Dinucleotide, Glutathione, Heart Diseases, Humans, Mice, Transgenic, Mitochondria, Heart, Myocardium, NAD, Ventricular Function, Left, Cell Respiration, Cytoprotection, Mitochondrial Proteins, Myocytes, Cardiac, Cytochromes c, BH3 Interacting Domain Death Agonist Protein, Mice, Glutaredoxins

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