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.
Highlights
Diabetes is one of the major risk factors for the development of cardiovascular complications
Recent studies demonstrated that myocardial heart failure is associated with increased oxidative stress and abnormal excitation-contraction coupling (ECC) characterized by depletion of sarcoplasmic reticulum (SR) Ca2+ stores and reduction in Ca2+-transient amplitude associated with oxidative modification of thiols in both SR Ca2+-ATPase (SERCA) and Na+/Ca2+-exchanger (NCX) [6,7]
In both early and recent studies, depression in contraction and relaxation of cardiomyocytes from streptozotocin (STZ)-induced diabetic rats were found in parallel with reduced rate of rise and decline of intracellular Ca2+ transient elicited by electrical stimulation which were mostly attributed to anomalous SERCA and phospholamban (PLN) activities, hyperphosphorylation of SR Ca2+ release channel ryanodine receptors (RyR2), and in part to reduced NCX activity [3,10,11,12,13,14]
Summary
Diabetes is one of the major risk factors for the development of cardiovascular complications. There are some contradictions between the experimental results in the literature, it is pointed out that increased oxidative stress, induced by reactive oxygen and nitrogen species (ROS/RNS) derived via hyperglycemia, has important contribution, directly and/or indirectly, to the structural and functional damages in the diabetic cardiomyocytes [8,9] In both early and recent studies, depression in contraction and relaxation of cardiomyocytes from streptozotocin (STZ)-induced diabetic rats were found in parallel with reduced rate of rise and decline of intracellular Ca2+ transient elicited by electrical stimulation which were mostly attributed to anomalous SERCA and phospholamban (PLN) activities, hyperphosphorylation of SR Ca2+ release channel ryanodine receptors (RyR2), and in part to reduced NCX activity [3,10,11,12,13,14]
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