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Hyperglycemia-induced changes in ZIP7 and ZnT7 expression cause Zn2+ release from the sarco(endo)plasmic reticulum and mediate ER-stress in the heart

Tuncay, Erkan, Bitirim, Verda C., Durak, Aysegul, Carrat, Gaelle R.J., Taylor, Kathryn, Rutter, Guy A. and Turan, Belma 2017. Hyperglycemia-induced changes in ZIP7 and ZnT7 expression cause Zn2+ release from the sarco(endo)plasmic reticulum and mediate ER-stress in the heart. Diabetes 66 (5) , pp. 1346-1358. 10.2337/db16-1099

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Abstract

Changes in cellular free Zn2+ concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn2+ transporters (ZnTs) whose identity and role in the heart are not well established. 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 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 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 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 Zn2+ redistribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Diabetes Association
ISSN: 0012-1797
Date of First Compliant Deposit: 4 September 2017
Date of Acceptance: 10 February 2017
Last Modified: 12 Jan 2018 01:09
URI: http://orca.cf.ac.uk/id/eprint/104314

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