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Selenium prevents diabetes-induced alterations in [Zn²⁺]_i and metallothionein level of rat heart via restoration of cell redox cycle

Department of Biophysics, School of Medicine, Ankara University, Ankara, Turkey

Submitted 15 July 2005 ; accepted in final form 8 September 2005

Intracellular free zinc concentration ([Zn²⁺]_i) is very important for cell functions, and its excessive accumulation is cytotoxic. [Zn²⁺]_i can increase rapidly in cardiomyocytes because of mobilization of Zn²⁺ from intracellular stores by reactive oxygen species (ROS). Moreover, ROS have been proposed to contribute to direct and/or indirect damage to cardiomyocytes in diabetes. To address these hypotheses, we investigated how elevated [Zn²⁺]_i in cardiomyocytes could contribute to diabetes-induced alterations in intracellular free calcium concentration ([Ca²⁺]_i). We also investigated its relationship to the changes of metallothionein (MT) level of the heart. Cardiomyocytes from normal rats loaded with fura-2 were used to fluorometrically measure resting [Zn²⁺]_i (0.52 ± 0.06 nM) and [Ca²⁺]_i (26.53 ± 3.67 nM). Fluorescence quenching by the heavy metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine was used to quantify [Zn²⁺]_i. Our data showed that diabetic cardiomyocytes exhibited significantly increased [Zn²⁺]_i (0.87 ± 0.05 nM ) and [Ca²⁺]_i (49.66 ± 9.03 nM), decreased levels of MT and reduced glutathione, increased levels of lipid peroxidation and nitric oxide products, and decreased activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Treatment (4 wk) of diabetic rats with sodium selenite (5 µmol·kg body wt^–1·day^–1) prevented these defects induced by diabetes. A comparison of present data with previously observed beneficial effects of selenium treatment on diabetes-induced contractile dysfunction of the heart can suggest that an increase in [Zn²⁺]_i may contribute to oxidant-induced alterations of excitation-contraction coupling in diabetes. In addition, we showed that oxidative stress is involved in the etiology of diabetes-induced downregulation of heart function via depressed endogenous antioxidant defense mechanisms.

intracellular zinc; intracellular calcium; Type 1 diabetes; antioxidant; oxidant stress