Metallothionein Prevents Diabetes-Induced Deficits in Cardiomyocytes by Inhibiting Reactive Oxygen Species Production
Open accessAbstract
Many individuals with diabetes experience impaired cardiac contractility that cannot be explained by hypertension and atherosclerosis. This cardiomyopathy may be due to either organ-based damage, such as fibrosis, or to direct damage to cardiomyocytes. Reactive oxygen species (ROS) have been proposed to contribute to such damage. To address these hypotheses, we examined contractility, Ca2+ handling, and ROS levels in individual cardiomyocytes isolated from control hearts, diabetic OVE26 hearts, and diabetic hearts overexpressing antioxidant protein metallothionein (MT). Our data showed that diabetic myocytes exhibited significantly reduced peak shortening, prolonged duration of shortening/relengthening, and decreased maximal velocities of shortening/relengthening as well as slowed intracellular Ca2+ decay compared with control myocytes. Overexpressing MT prevented these defects induced by diabetes. In addition, high glucose and angiotensin II promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of MT or acute in vitro treatment with the flavoprotein inhibitor diphenyleneiodonium or the angiotensin II type I receptor antagonist losartan eliminated excess ROS production in diabetic cardiomyocytes. These data show that diabetes induces damage at the level of individual myocyte. Damage can be attributed to ROS production, and diabetes increases ROS production via angiotensin II and flavoprotein enzyme-dependent pathways.
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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
- Ye, G., Metreveli, N. S., Ren, J., & Epstein, P. N.
- Affiliations
- University of Louisville (US)
- University of North Dakota (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2003-03-01
- Volume
- 52
- Issue
- 3
- Pages
- 777-783
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2135140753
- Cited by
- 180
- References
- 42
- Citations by year
- 2024: 3 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 7 · 2012: 16
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 6677, R01HL062892, HL-62892)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- metallothionein, diabetic cardiomyopathy, reactive oxygen species, cardiomyocyte contractility, calcium handling, angiotensin II, angiotensin II type 1 receptor, diphenyleneiodonium, losartan, high glucose
- MeSH terms
- Angiotensin II, Animals, Calcium, Diabetes Mellitus, Enzyme Inhibitors, Glucose, Metallothionein, Mice, Transgenic, Myocardial Contraction, Myocardium, Onium Compounds, Spectrometry, Fluorescence, Gene Expression, Reactive Oxygen Species, NADPH Oxidases, Losartan, Receptor, Angiotensin, Type 1, Diabetes Complications, Mice, Angiotensin Receptor Antagonists
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