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Overexpression of metallothionein reduces diabetic cardiomyopathy
Qiangrong Liang1, Edward C Carlson, Rajakumar V Donthi
1Division of Molecular Cardiovascular Biology, University of Cincinnati, Ohio, USA.
Insights
Diabetic cardiomyopathy, a precursor to heart failure, can be mitigated by antioxidant proteins. Overexpressing metallothionein (MT) in diabetic mouse hearts reduced oxidative stress and improved cardiac function, demonstrating its protective effects.
Area of Science:
- Cardiology
- Endocrinology
- Molecular Biology
Background:
- Diabetic cardiomyopathy is a significant complication in diabetes mellitus, increasing the risk of heart failure and mortality.
- Oxidative stress, indicated by elevated oxidized glutathione (GSSG), is implicated in the pathogenesis of diabetic cardiomyopathy.
- Metallothionein (MT) is an antioxidant protein with potential protective roles in cardiac conditions.
Purpose of the Study:
- To investigate the efficacy of cardiac-specific overexpression of the antioxidant protein metallothionein (MT) in ameliorating diabetic cardiomyopathy.
- To determine if elevated MT levels can counteract oxidative stress and improve cardiac function in a mouse model of diabetes.
Main Methods:
- Utilized OVE26 transgenic mice, a model for type 1 diabetes, and crossed them with MT-overexpressing transgenic mice to create OVE26MT mice.
- Assessed cardiac function, morphology, mRNA expression, and levels of oxidized glutathione (GSSG) in diabetic (OVE26) and OVE26MT mice.
- Compared OVE26MT mice with OVE26 mice, noting similar hyperglycemia levels between the groups.
Main Results:
- Diabetic OVE26 mice exhibited characteristic cardiomyopathy, including altered mRNA, morphological abnormalities, and impaired contractility under ischemia.
- OVE26MT mice, despite having similar hyperglycemia, showed significantly reduced cardiomyopathy compared to OVE26 mice.
- Elevated cardiac MT in OVE26MT mice normalized mRNA levels, reduced GSSG, preserved normal heart morphology, and improved impaired ischemic contractility.
Conclusions:
- Cardiomyocyte-specific expression of the antioxidant protein metallothionein (MT) effectively reduces cardiac damage in a mouse model of diabetes.
- Targeting oxidative stress through antioxidant protein overexpression represents a promising therapeutic strategy for diabetic cardiomyopathy.
- These findings highlight the protective role of MT against diabetes-induced cardiac dysfunction.
Abstract:
Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart.