Changes in cellular free Zn2+ concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn2+-transporters whose identity and role in the heart is not well established. Here, we hypothesized that ZIP7 and ZnT7 transport Zn2+ in opposing directions across the S(E)R membrane in cardiomyocytes and that changes in their activity may 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 whilst ZnT7 expression was low. Additionally, we observed increased ZIP7-phosphorylation in response to high glucose in vivo and in vitro. Using recombinant targeted FRET-based sensors, we showed that hyperglycemia induced a marked redistribution of cellular free Zn2+, increasing cytosolic free Zn2+ and lowering free Zn2+ in the S(E)R. These changes involve alterations in ZIP7-phosphorylation and were suppressed by siRNA-mediated silencing of CK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed in hyperglycemia. We conclude that sub-cellular free Zn2+ re-distribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1099/-/DC1.
- Received September 10, 2016.
- Accepted February 9, 2017.
- © 2017 by the American Diabetes Association.