title: Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart.
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.
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
authors.forename: Erkan
authors.initials: E
authors.lastname: Tuncay
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
authors.forename: Verda C
authors.initials: VC
authors.lastname: Bitirim
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Durak
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Gaelle R J
authors.initials: GRJ
authors.lastname: Carrat
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff, U.K.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Taylor
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, U.K.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey belma.turan@medicine.ankara.edu.tr g.rutter@imperial.ac.uk.
authors.forename: Belma
authors.initials: B
authors.lastname: Turan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047390:Casein Kinase II / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D006352:Heart Ventricles / Q000166:cytology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; C000592025:Slc30A7 protein, rat; D047390:Casein Kinase II; D015032:Zinc