Abstract
Zinc exists in biological system and resting intracellular level of free Zn2+ ([Zn2+]i) can be greatly increased by thiol-reactive oxidants or high glucose and contributes to oxidant-induced alterations in EC-coupling although in cardiomyocytes. Since [Zn2+]i is altering function of numerous cellular proteins, its mobilization by reactive oxygen species in diabetic heart can be likely to cause significant effects. Therefore, we aimed to investigate the role of antioxidant-defence system in preserving of cardiac ryanodine receptor (RyR2) function via regulation of both [Zn2+]i and [Ca2+]i homeostasis in hyperglycemic cardiomyocytes. We used freshly isolated cardiomyocytes from a rat model of chronic diabetes induced by streptozotocin either treated or untreated with an antioxidant N-acetyl cysteine (NAC; 1.5 mg/kg, daily; for 4 weeks). We used cytosolic Ca2+ and Zn2+ dyes (Fluo-3AM and FluoZin-3AM, respectively) to measure both Zn2+ and Ca2+ sparks, their transient changes under electrical or caffeine stimulation, and the resting levels of both [Zn2+]i and [Ca2+]i in the loaded cells. We obtained significantly increased resting levels of [Zn2+]i and [Ca2+]i, impairments in the parameters of both global and transient fluorescence changes in diabetic cardiomyocytes while these were found to be preserved in the in vivo and in vitro NAC-treated diabetic cardiomyocytes. Free protein-sulfhydryls in isolated diabetic cardiomyocytes were measured to be significantly decreased compared to those of the both controls and NAC-treated diabetics. Furthermore our results have demonstrated that intracellular Zn2+ induces marked phosphorylation and dysfunction in the RyR2, while these were preserved with NAC-treatment. Overall, the present data suggest that the changes under hyperglycemia not only in [Ca2+]i but also [Zn2+]i play important role in RyR2 function, in part via hyperglycemia-induced increased oxidative stress and depressed antioxidant-defence system in cardiomyocytes. (Supported by TUBITAK-SBAG-109S267&111S042)
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