title: Enhancement of cellular antioxidant-defence preserves diastolic dysfunction via regulation of both diastolic Zn2+ and Ca2+ and prevention of RyR2-leak in hyperglycemic cardiomyocytes.
abstract: We examined whether cellular antioxidant-defence enhancement preserves diastolic dysfunction via regulation of both diastolic intracellular free Zn(2+) and Ca(2+) levels ([Zn(2+)]i and [Ca(2+)]i) levels N-acetyl cysteine (NAC) treatment (4 weeks) of diabetic rats preserved altered cellular redox state and also prevented diabetes-induced tissue damage and diastolic dysfunction with marked normalizations in the resting [Zn(2+)]i and [Ca(2+)]i. The kinetic parameters of transient changes in Zn(2+) and Ca(2+) under electrical stimulation and the spatiotemporal properties of Zn(2+) and Ca(2+) sparks in resting cells are found to be normal in the treated diabetic group. Biochemical analysis demonstrated that the NAC treatment also antagonized hyperphosphorylation of cardiac ryanodine receptors (RyR2) and significantly restored depleted protein levels of both RyR2 and calstabin2. Incubation of cardiomyocytes with 10 µM ZnCl2 exerted hyperphosphorylation in RyR2 as well as higher phosphorphorylations in both PKA and CaMKII in a concentration-dependent manner, similar to hyperglycemia. Our present data also showed that a subcellular oxidative stress marker, NF-κB, can be activated if the cells are exposed directly to Zn(2+). We thus for the first time report that an enhancement of antioxidant defence in diabetics via directly targeting heart seems to prevent diastolic dysfunction due to modulation of RyR2 macromolecular-complex thereby leading to normalized [Ca(2+)]i and [Zn(2+)]i in cardiomyocytes.
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara 06100, Turkey.
authors.forename: Erkan
authors.initials: E
authors.lastname: Tuncay
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara 06100, Turkey.
authors.forename: Esma N
authors.initials: EN
authors.lastname: Okatan
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara 06100, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Toy
authors.affiliation: Department of Biophysics, Faculty of Medicine, Ankara University, Ankara 06100, Turkey.
authors.forename: Belma
authors.initials: B
authors.lastname: Turan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D016328:NF-kappa B; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D015032:Zinc; D002118:Calcium; D000111:Acetylcysteine