Inhibition of Superoxide Generation and Associated Nitrosative Damage Is Involved in Metallothionein Prevention of Diabetic Cardiomyopathy
Open accessAbstract
The mechanisms of metallothionein prevention of diabetic cardiomyopathy are largely unknown. The present study was performed to test whether inhibition of nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice and wild-type littermate controls were treated with streptozotocin (STZ) by a single intraperitoneal injection, and both developed diabetes. However, the development of diabetic cardiomyopathy, revealed by histopathological and ultrastructural examination, serum creatine phosphokinase, and cardiac hemodynamic analysis, was significantly observed only in the wild-type, but not in MT-TG, diabetic mice 2 weeks and 6 months after STZ treatment. Formations of superoxide and 3-nitrotyrosine (3-NT), a marker for peroxynitrite-induced protein damage, were detected only in the heart of wild-type diabetic mice. Furthermore, primary cultures of cardiomyocytes from wild-type and MT-TG mice were exposed to lipopolysaccharide/tumor necrosis factor-α for generating intracellular peroxynitrite. Increases in 3-NT formation and cytotoxicity were observed in wild-type, but not in MT-TG, cardiomyocytes. Either urate, a peroxynitrite-specific scavenger, or Mn(111) tetrakis 1-methyl 4-pyridyl porphyrin pentachloride (MnTMPyP), a superoxide dismutase mimic, significantly inhibited the formation of 3-NT along with a significant prevention of cytotoxicity. These results thus suggest that metallothionein prevention of diabetic cardiomyopathy is mediated, at least in part, by suppression of superoxide generation and associated nitrosative damage.
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Lowering iron improves insulin sensitivity, and metallothionein is protective.
“Lowering iron improves insulin sensitivity [598,614], and metallothionein is also protective [615-619].”
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- Authors
- Cai, L., Wang, J., Li, Y., Sun, X., Wang, L., Zhou, Z., & Kang, Y. J.
- Affiliations
- University of Louisville (US)
- Department of Medicine, University of Louisville, School of Medicine, Louisville, Kentucky
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-06-01
- Volume
- 54
- Issue
- 6
- Pages
- 1829-1837
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2158200096
- Cited by
- 199
- References
- 49
- Citations by year
- 2025: 1 · 2024: 7 · 2023: 1 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 17 · 2016: 15 · 2015: 11 · 2014: 16 · 2013: 14 · 2012: 13
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- University of Louisville
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R21AA013601)
- National Heart, Lung, and Blood Institute (HL 59225, R01HL063760, HL 63760, R01HL059225)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- metallothionein, diabetic cardiomyopathy, superoxide production, nitrosative damage, peroxynitrite, nitrotyrosine, streptozotocin-induced diabetes, cardiac-specific transgenic mice, cardiomyocyte injury, uric acid, MnTMPyP, superoxide dismutase mimetic
- MeSH terms
- Animals, Heart Diseases, Male, Metallothionein, Mice, Transgenic, Cardiomyopathies, Superoxides, Tyrosine, Nitrosation, Gene Expression, Diabetes Complications, Mice
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