Attenuation of doxorubicin-induced cardiac injury by mitochondrial glutaredoxin 2
Open accessAbstract
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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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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Redox regulation of mitochondrial function
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Protein glutathionylation in health and disease
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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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1663 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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