Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn 2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart
Changes in cellular free Zn concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn transporters (ZnTs) whose identity and role in the heart are not well established. We hypothesized that ZIP7 and ZnT7 transport Zn in opposing directions across the...
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Published in | Diabetes (New York, N.Y.) Vol. 66; no. 5; p. 1346 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.05.2017
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Subjects | |
Online Access | Get full text |
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Summary: | Changes in cellular free Zn
concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn
transporters (ZnTs) whose identity and role in the heart are not well established. We hypothesized that ZIP7 and ZnT7 transport Zn
in opposing directions across the S(E)R membrane in cardiomyocytes and that changes in their activity play an important role in the development of ER stress during hyperglycemia. The subcellular S(E)R localization of ZIP7 and ZnT7 was determined in cardiomyocytes and in isolated S(E)R preparations. Markedly increased mRNA and protein levels of ZIP7 were observed in ventricular cardiomyocytes from diabetic rats or high-glucose-treated H9c2 cells while ZnT7 expression was low. In addition, we observed increased ZIP7 phosphorylation in response to high glucose in vivo and in vitro. By using recombinant-targeted Förster resonance energy transfer sensors, we show that hyperglycemia induces a marked redistribution of cellular free Zn
, increasing cytosolic free Zn
and lowering free Zn
in the S(E)R. These changes involve alterations in ZIP7 phosphorylation and were suppressed by small interfering RNA-mediated silencing of CK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed in hyperglycemia. We conclude that subcellular free Zn
redistribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes. |
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ISSN: | 1939-327X |