Attenuation by Metallothionein of Early Cardiac Cell Death via Suppression of Mitochondrial Oxidative Stress Results in a Prevention of Diabetic Cardiomyopathy
Open accessAbstract
Objectives We aimed to test whether attenuation of early-phase cardiac cell death can prevent diabetic cardiomyopathy. Background Our previous study showed that cardiac apoptosis as a major early cellular response to diabetes is induced by hyperglycemia-derived oxidative stress that activates a mitochondrial cytochrome c-mediated caspase-3 activation pathway. Metallothionein (MT) as a potent antioxidant prevents the development of diabetic cardiomyopathy. Methods Diabetes was induced by a single dose of streptozotocin (STZ) (150 mg/kg) in cardiac-specific, metallothionein-overexpressing transgenic (MT-TG) mice and wild-type (WT) controls. On days 7, 14, and 21 after STZ treatment, cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activation. Cardiomyopathy was evaluated by cardiac ultrastructure and fibrosis in the diabetic mice 6 months after STZ treatment. Results A significant reduction in diabetes-induced increases in TUNEL-positive cells, caspase-3 activation, and cytochrome c release from mitochondria was observed in the MT-TG mice as compared to WT mice. Cardiac protein nitration (3-nitrotyrosine [3-NT]) and lipid peroxidation were significantly increased, and there was an increase in mitochondrial oxidized glutathione and a decrease in mitochondrial reduced glutathione in the WT, but not in the MT-TG, diabetic mice. Double staining for cardiomyocytes with alpha sarcomeric actin and caspase-3 or 3-NT confirmed the cardiomyocyte-specific effects. A significant prevention of diabetic cardiomyopathy and enhanced animal survival were observed in the MT-TG diabetic mice as compared to WT diabetic mice. Conclusions These results suggest that attenuation of early-phase cardiac cell death by MT results in a significant prevention of the development of diabetic cardiomyopathy. This process is mediated by MT suppression of mitochondrial oxidative stress.
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Multiple studies have established a link between damage induced by oxidative stress and DCM.
“Multiple studies have established a link between damage induced by oxidative stress and DCM [12, 13].”
From Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population (2016) · cites this paper as [12]
Damage from oxidative stress due to chronic mitochondrial overproduction of reactive oxygen species (ROS) plays a crucial role in inflammation and results in irreversible fibrosis and cardiomyocyte death.
“Damage from oxidative stress due to the chronic mitochondrial overproduction of reactive oxygen species (ROS) plays a crucial role in inflammation and results in irreversible fibrosis and cardiomyocyte death [2, 12, 14, 15].”
From Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population (2016) · cites this paper as [12]
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“Amelioration of oxidative stress on a molecular level can be achieved through induction of antioxidant agents, and studies have shown that enhancing mitochondrial ROS scavenging systems mitigates diabetes-induced cardiac dysfunction [2, 12, 18-21].”
- Authors
- Cai, L., Wang, Y., Zhou, G., Chen, T., Song, Y., Li, X., & Kang, Y. J.
- Affiliations
- University of Louisville (US)
- Wenzhou Medical University (CN)
- Corresponding author
- Cai, Lu
- Li, Xiaokun
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 48
- Issue
- 8
- Pages
- 1688-1697
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W1992564227
- Cited by
- 378
- References
- 4
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 23 · 2023: 12 · 2022: 16 · 2021: 14 · 2020: 21 · 2019: 15 · 2018: 24 · 2017: 29 · 2016: 21 · 2015: 30 · 2014: 25 · 2013: 28 · 2012: 22
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (HL59225)
- National Heart, Lung, and Blood Institute (HL 59225, R01HL063760, HL 63760, R01HL059225)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- metallothionein, diabetic cardiomyopathy, cardiac apoptosis, mitochondrial oxidative stress, caspase-3 activation, cytochrome c release, streptozotocin-induced diabetes, nitrotyrosine, lipid peroxidation, glutathione, myocardial fibrosis, hyperglycemia
- MeSH terms
- Actins, Animals, Antioxidants, Diabetes Mellitus, Experimental, Enzyme Activation, Glutathione, Metallothionein, Mice, Transgenic, Mitochondria, Heart, Cardiomyopathies, Myocardium, Sarcomeres, Tyrosine, Lipid Peroxidation, Survival Analysis, Cell Death, Apoptosis, Oxidative Stress, Glutathione Disulfide, Myocytes, Cardiac, Cytochromes c, Mice, Caspase 3
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