ß-Blocker Timolol Prevents Arrhythmogenic Ca2+ Release and Normalizes Ca2+ and Zn2+ Dyshomeostasis in Hyperglycemic Rat Heart


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TUNCAY E., Okatan E. N. , Vassort G., TURAN B.

PLoS ONE, vol.8, no.7, 2013 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 8 Issue: 7
  • Publication Date: 2013
  • Doi Number: 10.1371/journal.pone.0071014
  • Title of Journal : PLoS ONE

Abstract

Defective cardiac mechanical activity in diabetes results from alterations in intracellular Ca2+ handling, in part, due to increased oxidative stress. Beta-blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant. The aim of this study was to address how β-blocker timolol-treatment of diabetic rats exerts cardioprotection. Timolol-treatment (12-week), one-week following diabetes induction, prevented diabetes-induced depressed left ventricular basal contractile activity, prolonged cellular electrical activity, and attenuated the increase in isolated-cardiomyocyte size without hyperglycemic effect. Both in vivo and in vitro timolol-treatment of diabetic cardiomyocytes prevented the altered kinetic parameters of Ca2+ transients and reduced Ca2+ loading of sarcoplasmic reticulum (SR), basal intracellular free Ca2+ and Zn2+ ([Ca2+]i and [Zn2+]i), and spatio-temporal properties of the Ca2+ sparks, significantly. Timolol also antagonized hyperphosphorylation of cardiac ryanodine receptor (RyR2), and significantly restored depleted protein levels of both RyR2 and calstabin2. Western blot analysis demonstrated that timolol-treatment also significantly normalized depressed levels of some [Ca2+]i-handling regulators, such as Na+/Ca2+ exchanger (NCX) and phospho-phospholamban (pPLN) to PLN ratio. Incubation of diabetic cardiomyocytes with 4-mM glutathione exerted similar beneficial effects on RyR2-macromolecular complex and basal levels of both [Ca2+]i and [Zn2+]i, increased intracellular Zn2+ hyperphosphorylated RyR2 in a concentration-dependent manner. Timolol also led to a balanced oxidant/antioxidant level in both heart and circulation and prevented altered cellular redox state of the heart. We thus report, for the first time, that the preventing effect of timolol, directly targeting heart, seems to be associated with a normalization of macromolecular complex of RyR2 and some Ca2+ handling regulators, and prevention of Ca2+ leak, and thereby normalization of both [Ca2+]i and [Zn2+]i homeostasis in diabetic rat heart, at least in part by controlling the cellular redox status of hyperglycemic cardiomyocytes. © 2013 Tuncay et al.