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 Zn
2+ re-distribution in the hyperglycemic
heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in
diabetes.