|Wang, Jianxun - UNIV OF LOUISVILLE, KY|
|Song, Ye - UNIV OF LOUISVILLE, KY|
|Elsherif, Laila - UNIV OF LOUISVILLE, KY|
|Sun, Xiuhua - UNIV OF LOUISVILLE, KY|
|Mcclain, Craig - UNIV LOUISVILLE/VET ADMIN|
|Kang, Y - UNIV OF LOUISVILLE, KY|
|Cai, Lu - UNIV OF LOUISVILLE, KY|
Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 28, 2005
Publication Date: January 23, 2006
Citation: Wang, J., Song, Y., Elsherif, L., Song, Z., Zhou, G., Prabhu, S.D., Saari, J.T., Cai, L. 2006. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation. 113:544-554. Interpretive Summary: Metallothionein is a protein that exists in low concentrations in all tissues. It acts as a detoxifying agent and, under such conditions as heavy metal poisoning and oxidative stress, metallothionein concentration is increased. Diabetes is a disease that can impair heart function and is associated with oxidative damage. Previous studies have shown that experimentally increasing the amount of metallothionein in the heart can inhibit the heart damage caused by diabetes. Because metallothionein is the primary carrier for zinc in the body, a method of benignly elevating metallothionein concentration is to raise the body's zinc concentration. To determine whether elevating metallothionein in this way could prevent the cardiac damage of diabetes, we injected diabetic rats with zinc and found that both structural and functional changes in diabetic hearts were reduced by zinc injection. Further, damage to heart cells in culture caused by high sugar concentrations was not prevented by high zinc concentration if metallothionein production was genetically impaired. These findings suggest the potential for protecting diabetic hearts by elevation of heart metallothionein through increasing the body's zinc concentration.
Technical Abstract: Background: Our previous study showed that cardiac-specific metallothionein (MT)-overexpressing transgenic mice were highly resistant to diabetes-caused cardiomyopathy. Zinc is the major metal to which MT binds under physiological condition and is a potent inducer for MT. The present study, therefore, was undertaken to explore whether zinc supplementation can protect against diabetic cardiomyopathy through cardiac MT induction. In addition, cardiac cells were directly exposed to high levels of glucose (HG) and free fatty acid (FFA, palmitate) to mimic diabetic conditions to further define the role of MT in the cardiac protection by zinc supplementation. Methods and Results: Diabetes was induced by a single injection of streptozotocin in C57BL/6J mice. Diabetic mice were supplemented intraperitoneally with zinc sulfate (5mg/kg) every other day over a period of 3 months. At the end of zinc supplementation, these mice were kept 3 more months and then cardiomyopathy was examined by functional and morphological analysis. Significant increases in morphological abnormalities and reduced contractility were observed in the diabetic mice without zinc supplementation, but not in the diabetic mice with 3-month zinc supplementation. Three-month zinc supplementation also induced a significant increase in cardiac MT expression. Using cardiac cell cultures, it was found that in response to HG/FFA, cell survival rate significantly decreased, but was significantly prevented by zinc or by low-dose cadmium, both of which induced significant MT synthesis. Furthermore, using siRNA strategy to silence MT transcriptional expression, cells pre-treated by zinc did not show the same resistance to the damaging effects of HG/FFA. Conclusion: These results suggest that the prevention of diabetic cardiomyopathy by zinc supplementation is predominantly mediated by increased cardiac MT.